Pinane-substituted pyrimidinediamine derivatives useful as axl inhibitors

ABSTRACT

Pinane-substituted pyrimidinediamine derivatives and pharmaceutical compositions containing the derivatives are disclosed as being useful in inhibiting the activity of the receptor protein tyrosine kinase Axl. Methods of using the derivatives in treating diseases or conditions associated with Axl catalytic activity are also disclosed.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional of U.S. patent application Ser. No.11/870,362, filed Oct. 10, 2007 (now allowed); which claims the benefitunder 35 U.S.C. §119(e) of U.S. Provisional Patent Application No.60/850,741 filed Oct. 10, 2006. These applications are incorporatedherein by reference in their entireties.

FIELD OF THE INVENTION

This invention is directed to pinane-substituted pyrimidinediaminederivatives and pharmaceutical compositions thereof which are useful asinhibitors of the receptor protein tyrosine kinase known as Axl. Thisinvention is also directed to methods of using the derivatives andcompositions in treating diseases and conditions associated with Axlactivity, particularly in treating diseases and conditions associatedwith angiogenesis and/or cell proliferation.

BACKGROUND OF THE INVENTION

All of the protein kinases that have been identified to date in thehuman genome share a highly conserved catalytic domain of around 300 aa.This domain folds into a bi-lobed structure in which reside ATP-bindingand catalytic sites. The complexity of protein kinase regulation allowsmany potential mechanisms of inhibition including competition withactivating ligands, modulation of positive and negative regulators,interference with protein dimerization, and allosteric or competitiveinhibition at the substrate or ATP binding sites.

Axl (also known as UFO, ARK, and Tyro7; nucleotide accession numbersNM_(—)021913 and NM_(—)001699; protein accession numbers NP_(—)068713and NP_(—)001690) is a receptor protein tyrosine kinase (RTK) thatcomprises a C-terminal extracellular ligand-binding domain andN-terminal cytoplasmic region containing the catalytic domain. Theextracellular domain of Axl has a unique structure that juxtaposesimmunoglobulin and fibronectin Type III repeats and is reminiscent ofthe structure of neural cell adhesion molecules. Axl and its two closerelatives, Mer/Nyk and Sky (Tyro3/Rse/Dtk), collectively known as theTyro3 family of RTKs, all bind and are stimulated to varying degrees bythe same ligand, Gas6 (growth arrest specific-6), a ˜76 kDa secretedprotein with significant homology to the coagulation cascade regulator,Protein S. In addition to binding to ligands, the Axl extracellulardomain has been shown to undergo homophilic interactions that mediatecell aggregation, suggesting that one important function of Axl may beto mediate cell-cell adhesion.

Axl is predominantly expressed in the vasculature in both endothelialcells (EC's) and vascular smooth muscle cells (VSMC's) and in cells ofthe myeloid lineage and is also detected in breast epithelial cells,chondrocytes, Sertoli cells and neurons. Several functions includingprotection from apoptosis induced by serum starvation, TNF-α or theviral protein EIA, as well as migration and cell differentiation havebeen ascribed to Axl signaling in cell culture. However, Axl−/− miceexhibit no overt developmental phenotype and the physiological functionof Axl in vivo is not clearly established in the literature.

Angiogenesis (the formation of new blood vessels) is limited tofunctions such as wound healing and the female reproductive cycle inhealthy adults. This physiological process has been co-opted by tumors,thus securing an adequate blood supply that feeds tumor growth andfacilitates metastasis. Deregulated angiogenesis is also a feature ofmany other diseases (for example, psoriasis, rheumatoid arthritis,endometriosis and blindness due to age-related macular degeneration(AMD), retinopathy of prematurity and diabetes) and often contributes tothe progression or pathology of the condition.

The overexpression of Axl and/or its ligand has also been reported in awide variety of solid tumor types including, but not limited to, breast,renal, endometrial, ovarian, thyroid, non-small cell lung carcinoma, anduveal melanoma as well as in myeloid leukemias. Furthermore, itpossesses transforming activity in NIH3T3 and 32D cells. It has beendemonstrated that loss of Axl expression in tumor cells blocks thegrowth of solid human neoplasms in an in vivo MDA-MB-231 breastcarcinoma xenograft model. Taken together, these data suggest Axlsignaling can independently regulate EC angiogenesis and tumor growthand thus represents a novel target class for tumor therapeuticdevelopment.

The expression of Axl and Gas6 proteins is upregulated in a variety ofother disease states including endometriosis, vascular injury and kidneydisease and Axl signaling is functionally implicated in the latter twoindications. Axl-Gas6 signaling amplifies platelet responses and isimplicated in thrombus formation. Axl may thus potentially represent atherapeutic target for a number of diverse pathological conditionsincluding solid tumors, including, but not limited to, breast, renal,endometrial, ovarian, thyroid, non-small cell lung carcinoma and uvealmelanoma; liquid tumors, including but not limited to, leukemias(particularly myeloid leukemias) and lymphomas; endometriosis, vasculardisease/injury (including but not limited to restenosis, atherosclerosisand thrombosis), psoriasis; visual impairment due to maculardegeneration; diabetic retinopathy and retinopathy of prematurity;kidney disease (including but not limited to glomerulonephritis,diabetic nephropathy and renal transplant rejection), rheumatoidarthritis, osteoarthritis and cataracts. There exists, therefore, a needfor small molecule inhibitors of Axl activity.

SUMMARY OF THE INVENTION

This invention is directed to certain pinane-substitutedpyrimidinediamine derivatives which are useful as Axl inhibitors,methods of using such derivatives in treating diseases and conditionsassociated with Axl activity and pharmaceutical compositions comprisingsuch derivatives.

Accordingly, in one aspect, this invention is directed to compounds offormula (Ia):

wherein:

-   n is 0 to 7;-   m is 0 to 2;-   R¹, R², R⁴ and R⁵ are each independently hydrogen, alkyl, aryl,    aralkyl, cycloalkyl, cycloalkylalkyl, —R¹⁴—OR¹⁵, —C(O)R¹⁵ or    —C(O)N(R¹¹)R¹²;-   or R⁴ and R⁵, together with the nitrogen to which they are attached,    form an optionally substituted N-heteroaryl or an optionally    substituted N-heterocyclyl;-   R^(1a), R^(3b), R^(3c), R^(3d) and R^(3e) are each independently    selected from the group consisting of hydrogen, alkyl, alkenyl,    alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, cyano, nitro,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted aralkenyl, optionally substituted aralkynyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted cycloalkylalkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, optionally substituted heteroarylalkynyl,    —R¹⁷—OR¹⁶, —R¹⁷—OC(O)—R¹⁶, —R¹⁷—N(R¹⁶)₂, —R¹⁷—C(O)R¹⁶,    —R¹⁷—C(O)OR¹⁶, —R¹⁷—C(O)N(R¹⁶)₂, —R¹⁷—O—R¹⁸—C(O)N(R¹⁶)₂,    —R¹⁷—O—R¹⁸—N(R¹⁶)₂, —R¹⁷—N(R¹⁶)C(O)OR¹⁶, —R¹⁷—N(R¹⁶)C(O)R¹⁶,    —R¹⁷—N(R¹⁶)S(O)_(t)R¹⁶ (where t is 1 or 2), —R¹⁷—S(O)_(t)OR¹⁶ (where    t is 1 or 2), —R¹⁷—S(O)_(p)R¹⁶ (where p is 0, 1 or 2), and    —R¹⁷—S(O)_(t)N(R¹⁶)₂ (where t is 1 or 2), where each R¹⁶ is    independently hydrogen, alkyl, haloalkyl, cycloalkyl,    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl or optionally    substituted heteroarylalkyl, each R¹⁷ is independently a direct bond    or a straight or branched alkylene or alkenylene chain, and R¹⁸ is a    straight or branched alkylene or alkenylene chain;-   R⁶, R⁷ and R⁸ are each independently alkyl, haloalkyl, or —R¹³—OR¹⁵;-   each R⁹ and R¹⁰ is independently alkyl, halo, haloalkyl, aryl or    aralkyl;-   R¹¹ and R¹² are each independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted    cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heterocyclylalkynyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, optionally    substituted heteroarylalkenyl, optionally substituted    heteroarylalkynyl, —R¹⁴—OR¹⁵, —R¹⁴—CN, —R¹⁴—NO₂, —R¹⁴—N(R¹⁵)₂,    —R¹⁴—C(O)OR¹⁵ and —R¹⁴—C(O)N(R¹⁵)₂;-   optionally, R¹¹ and R¹², together with the nitrogen to which they    are attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   R¹³ is independently selected from the group consisting of a direct    bond, an optionally substituted straight or branched alkylene chain,    an optionally substituted straight or branched alkenylene chain and    an optionally substituted straight or branched alkynylene chain;-   each R¹⁴ is independently selected from the group consisting of an    optionally substituted straight or branched alkylene chain, an    optionally substituted straight or branched alkenylene chain and an    optionally substituted straight or branched alkynylene chain; and-   each R¹⁵ is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,    haloalkynyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted aralkenyl, optionally substituted    aralkynyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted cycloalkylalkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl;    as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof.

Accordingly, in another aspect, this invention is directed to compoundsof formula (Ib):

wherein:

-   n is 0 to 7;-   m is 0 to 2;-   R¹, R², R⁴ and R⁵ are each independently hydrogen, alkyl, aryl,    aralkyl, cycloalkyl, cycloalkylalkyl, —R¹⁴—OR¹⁵, —C(O)R¹⁵ or    —C(O)N(R¹¹)R¹²;-   or R⁴ and R⁵, together with the nitrogen to which they are attached,    form an optionally substituted N-heteroaryl or an optionally    substituted N-heterocyclyl;-   R^(3a), R^(3b), R^(3c), R^(3d) and R^(3e) are each independently    selected from the group consisting of hydrogen, alkyl, alkenyl,    alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, cyano, nitro,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted aralkenyl, optionally substituted aralkynyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted cycloalkylalkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, optionally substituted heteroarylalkynyl,    —R¹⁷—OR¹⁶, —R¹⁷—OC(O)—R¹⁶, —R¹⁷—N(R¹⁶)₂, —R¹⁷—C(O)R¹⁶,    —R¹⁷—C(O)OR¹⁶, —R¹⁷—C(O)N(R¹⁶)₂, —R¹⁷—O—R¹⁸—C(O)N(R¹⁶)₂,    —R¹⁷—O—R¹⁸—N(R¹⁶)₂, —R¹⁷—N(R¹⁶)C(O)OR¹⁶, —R¹⁷—N(R¹⁶)C(O)R¹⁶,    —R¹⁷—N(R¹⁶)S(O)_(t)R¹⁶ (where t is 1 or 2), —R¹⁷—S(O)_(t)OR¹⁶ (where    t is 1 or 2), —R¹⁷—S(O)_(p)R¹⁶ (where p is 0, 1 or 2), and    —R¹⁷—S(O)_(t)N(R¹⁶)₂ (where t is 1 or 2), where each R¹⁶ is    independently hydrogen, alkyl, haloalkyl, cycloalkyl,    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl or optionally    substituted heteroarylalkyl, each R¹⁷ is independently a direct bond    or a straight or branched alkylene or alkenylene chain, and R¹⁸ is a    straight or branched alkylene or alkenylene chain;-   R⁶, R⁷ and R⁸ are each independently alkyl, haloalkyl, or —R¹³—OR¹⁵;-   each R⁹ and R¹⁰ is independently alkyl, halo, haloalkyl, aryl or    aralkyl;-   R¹¹ and R¹² are each independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted    cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heterocyclylalkynyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, optionally    substituted heteroarylalkenyl, optionally substituted    heteroarylalkynyl, —R¹⁴—OR¹⁵, —R¹⁴—CN, —R¹⁴—NO₂, —R¹⁴—N(R¹⁵)₂,    —R¹⁴—C(O)OR¹⁵ and —R¹⁴—C(O)N(R¹⁵)₂;-   optionally, R¹¹ and R¹², together with the nitrogen to which they    are attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   R¹³ is independently selected from the group consisting of a direct    bond, an optionally substituted straight or branched alkylene chain,    an optionally substituted straight or branched alkenylene chain and    an optionally substituted straight or branched alkynylene chain;-   each R¹⁴ is independently selected from the group consisting of an    optionally substituted straight or branched alkylene chain, an    optionally substituted straight or branched alkenylene chain and an    optionally substituted straight or branched alkynylene chain; and-   each R¹⁵ is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,    haloalkynyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted aralkenyl, optionally substituted    aralkynyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted cycloalkylalkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl;    as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof.

Accordingly, in another aspect, this invention is directed to compoundsof formula (Ic):

wherein:

-   n is 0 to 7;-   m is 0 to 2;-   q is 0 to 4;

Y is ═C(R^(3b))— or ═N—;

R¹, R², R⁴ and R⁵ are each independently hydrogen, alkyl, aryl, aralkyl,cycloalkyl, cycloalkylalkyl, —R¹⁴—OR¹⁵, —C(O)R¹⁵ or —C(O)N(R¹¹)R¹²;

-   or R⁴ and R⁵, together with the nitrogen to which they are attached,    form an optionally substituted N-heteroaryl or an optionally    substituted N-heterocyclyl;-   R^(3b) and R^(3e) are each independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, halo, haloalkyl,    haloalkenyl, haloalkynyl, cyano, nitro, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted    cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heterocyclylalkynyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, optionally    substituted heteroarylalkenyl, optionally substituted    heteroarylalkynyl, —R¹⁷—OR¹⁶, —R¹⁷—OC(O)—R¹⁶, —R¹⁷—N(R¹⁶)₂,    —R¹⁷—C(O)R¹⁶, —R¹⁷—C(O)OR¹⁶, —R¹⁷—C(O)N(R¹⁶)₂,    —R¹⁷—O—R¹⁶—C(O)N(R¹⁶)₂, —R¹⁷—O—R¹⁸—N(R¹⁶)₂, —R¹⁷—N(R¹⁶)C(O)OR¹⁶,    —R¹⁷—N(R¹⁶)C(O)R¹⁶, —R¹⁷—N(R¹⁶)S(O)P¹⁶ (where t is 1 or 2),    —R¹⁷—S(O)_(t)OR¹⁶ (where t is 1 or 2), —R¹⁷—S(O)_(p)R¹⁶ (where p is    0, 1 or 2), and —R¹⁷—S(O)_(t)N(R¹⁶)₂ (where t is 1 or 2), where each    R¹⁶ is independently hydrogen, alkyl, haloalkyl, cycloalkyl,    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl or optionally    substituted heteroarylalkyl, each R¹⁷ is independently a direct bond    or a straight or branched alkylene or alkenylene chain, and R¹⁸ is a    straight or branched alkylene or alkenylene chain;-   R^(3f) is independently selected from the group consisting of    hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted cycloalkyl, optionally    substituted cycloalkylalkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, —R¹⁴—OR¹⁵,    —R¹⁴—CN, —R¹⁴—NO₂, —R¹⁴—N(R¹⁵)₂, —R¹⁴—C(O)OR¹⁵ and —R¹⁴—C(O)N(R¹⁵)₂,    where each R¹⁴ is independently an optionally substituted straight    or branched alkylene chain and each R¹⁵ is independently selected    from the group consisting of hydrogen, alkyl, haloalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, and optionally    substituted heteroarylalkyl;-   each R^(3g) is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl,    haloalkynyl, cyano, nitro, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted aralkenyl, optionally    substituted aralkynyl, optionally substituted cycloalkyl, optionally    substituted cycloalkylalkyl, optionally substituted    cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heterocyclylalkynyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, optionally    substituted heteroarylalkenyl, optionally substituted    heteroarylalkynyl, —R¹⁷—OR¹⁶, —R¹⁷—OC(O)—R¹⁶, —R¹⁷—N(R¹⁶)₂,    —R¹⁷—C(O)R¹⁶, —R¹⁷—C(O)OR¹⁶, —R¹⁷—C(O)N(R¹⁶)₂,    —R¹⁷—O—R¹⁸—C(O)N(R¹⁶)₂, —R¹⁷—O—R¹⁸—N(R¹⁶)₂, —R¹⁷—N(R¹⁶)C(O)OR¹⁶,    —R¹⁷—N(R¹⁶)C(O)R¹⁶, —R¹⁷—N(R¹⁶)S(O)_(t)R¹⁶ (where t is 1 or 2),    —R¹⁷—S(O)_(t)OR¹⁶ (where t is 1 or 2), —R¹⁷—S(O)_(p)R¹⁶ (where p is    0, 1 or 2), and —R¹⁷—S(O)_(t)N(R¹⁶)₂ (where t is 1 or 2), where each    R¹⁶ is independently hydrogen, alkyl, haloalkyl, cycloalkyl,    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl or optionally    substituted heteroarylalkyl, each R¹⁷ is independently a direct bond    or a straight or branched alkylene or alkenylene chain, and R¹⁸ is a    straight or branched alkylene or alkenylene chain; or two R^(3g)'s,    together with the common carbon to which they are both attached,    form an oxo, or two R^(3g)'s on adjacent carbons form a double bond;-   R⁶, R⁷ and R⁸ are each independently alkyl, haloalkyl, or —R¹³—OR¹⁵;-   each R⁹ and R¹⁰ is independently alkyl, halo, haloalkyl, aryl or    aralkyl;-   R¹¹ and R¹² are each independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted    cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heterocyclylalkynyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, optionally    substituted heteroarylalkenyl, optionally substituted    heteroarylalkynyl, —R¹⁴—OR¹⁵, —R¹⁴—CN, —R¹⁴—NO₂, —R¹⁴—N(R¹⁵)₂,    —R¹⁴—C(O)OR¹⁵ and —R¹⁴—C(O)N(R¹⁵)₂;-   optionally, R¹¹ and R¹², together with the nitrogen to which they    are attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   R¹³ is independently selected from the group consisting of a direct    bond, an optionally substituted straight or branched alkylene chain,    an optionally substituted straight or branched alkenylene chain and    an optionally substituted straight or branched alkynylene chain;-   each R¹⁴ is independently selected from the group consisting of an    optionally substituted straight or branched alkylene chain, an    optionally substituted straight or branched alkenylene chain and an    optionally substituted straight or branched alkynylene chain; and-   each R¹⁵ is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,    haloalkynyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted aralkenyl, optionally substituted    aralkynyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted cycloalkylalkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl;    as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof.

Accordingly, in another aspect, this invention is directed to compoundsof formula (Id):

wherein:

-   n is 0 to 7;-   m is 0 to 2;-   q is 0 to 4;-   R¹, R², R⁴ and R⁵ are each independently hydrogen, alkyl, aryl,    aralkyl, cycloalkyl, cycloalkylalkyl, —R¹⁴—OR¹⁵, —C(O)R¹⁵ or    —C(O)N(R¹¹)R¹²;-   or R⁴ and R⁵, together with the nitrogen to which they are attached,    form an optionally substituted N-heteroaryl or an optionally    substituted N-heterocyclyl;-   R^(3b) and R^(3e) are each independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, halo, haloalkyl,    haloalkenyl, haloalkynyl, cyano, nitro, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted    cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heterocyclylalkynyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, optionally    substituted heteroarylalkenyl, optionally substituted    heteroarylalkynyl, —R¹⁷—OR¹⁶, —R¹⁷—OC(O)—R¹⁶, —R¹⁷—N(R¹⁶)₂,    —R¹⁷—C(O)R¹⁶, —R¹⁷—C(O)OR¹⁶, —R¹⁷—C(O)N(R¹⁶)₂,    —R¹⁷—O—R¹⁸—C(O)N(R¹⁶)₂, —R¹⁷—O—R¹⁸—N(R¹⁶)₂, —R¹⁷—N(R¹⁶)C(O)OR¹⁶,    —R¹⁷—N(R¹⁶)C(O)R¹⁶, —R¹⁷—N(R¹⁶)S(O)_(t)R¹⁶ (where t is 1 or 2),    —R¹⁷—S(O)_(t)OR¹⁶ (where t is 1 or 2), —R¹⁷—S(O)_(p)R¹⁶ (where p is    0, 1 or 2), and —R¹⁷—S(O)_(t)N(R¹⁶)₂ (where t is 1 or 2), where each    R¹⁶ is independently hydrogen, alkyl, haloalkyl, cycloalkyl,    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl or optionally    substituted heteroarylalkyl, each R¹⁷ is independently a direct bond    or a straight or branched alkylene or alkenylene chain, and R¹⁸ is a    straight or branched alkylene or alkenylene chain;-   R^(3f) is hydrogen, alkyl, haloalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heteroaryl, optionally substituted heteroarylalkyl,    —R¹⁴—OR¹⁵, —R¹⁴—CN, —R¹⁴—NO₂, —R¹⁴—N(R¹⁵)₂, —R¹⁴—C(O)OR¹⁵ and    —R¹⁴—C(O)N(R¹⁵)₂, where each R¹⁴ is independently an optionally    substituted straight or branched alkylene chain and each R¹⁵ is    independently selected from the group consisting of hydrogen, alkyl,    haloalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl,    and optionally substituted heteroarylalkyl;-   each R^(3g) is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl,    haloalkynyl, cyano, nitro, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted aralkenyl, optionally    substituted aralkynyl, optionally substituted cycloalkyl, optionally    substituted cycloalkylalkyl, optionally substituted    cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heterocyclylalkynyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, optionally    substituted heteroarylalkenyl, optionally substituted    heteroarylalkynyl, —R¹⁷—OR¹⁶, —R¹⁷—OC(O)—R¹⁶, —R¹⁷—N(R¹⁶)₂,    —R¹⁷—C(O)R¹⁶, —R¹⁷—C(O)OR¹⁶, —R¹⁷—C(O)N(R¹⁶)₂,    —R¹⁷—O—R¹⁸—C(O)N(R¹⁶)₂, —R¹⁷—O—R¹⁸—N(R¹⁶)₂, —R¹⁷—N(R¹⁶)C(O)OR¹⁶,    —R¹⁷—N(R¹⁶)C(O)R¹⁶, —R¹⁷—N(R¹⁶)S(O)_(t)R¹⁶ (where t is 1 or 2),    —R¹⁷—S(O)_(t)OR¹⁶ (where t is 1 or 2), —R¹⁷—S(O)_(p)R¹⁶ (where p is    0, 1 or 2), and —R¹⁷—S(O)_(t)N(R¹⁶)₂ (where t is 1 or 2), where each    R¹⁶ is independently hydrogen, alkyl, haloalkyl, cycloalkyl,    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl or optionally    substituted heteroarylalkyl, each R¹⁷ is independently a direct bond    or a straight or branched alkylene or alkenylene chain, and R¹⁸ is a    straight or branched alkylene or alkenylene chain; or two R^(3g)'s,    together with the common carbon to which they are both attached,    form an oxo, or two R^(3g)'s on adjacent carbons form a double bond;-   R⁶, R⁷ and R⁸ are each independently alkyl, haloalkyl, or —R¹³—OR¹⁵;-   each R⁹ and R¹⁰ is independently alkyl, halo, haloalkyl, aryl or    aralkyl;-   R¹¹ and R¹² are each independently selected from the group    consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,    haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted    cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heterocyclylalkynyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, optionally    substituted heteroarylalkenyl, optionally substituted    heteroarylalkynyl, —R¹⁴—OR¹⁵, —R¹⁴—CN, —R¹⁴—NO₂, —R¹⁴—N(R¹⁸)₂,    —R¹⁴—C(O)OR¹⁵ and —R¹⁴—C(O)N(R¹⁵)₂;-   optionally, R¹¹ and R¹², together with the nitrogen to which they    are attached, form an optionally substituted N-heteroaryl or an    optionally substituted N-heterocyclyl;-   R¹³ is independently selected from the group consisting of a direct    bond, an optionally substituted straight or branched alkylene chain,    an optionally substituted straight or branched alkenylene chain and    an optionally substituted straight or branched alkynylene chain;-   each R¹⁴ is independently selected from the group consisting of an    optionally substituted straight or branched alkylene chain, an    optionally substituted straight or branched alkenylene chain and an    optionally substituted straight or branched alkynylene chain; and-   each R¹⁵ is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,    haloalkynyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted aralkenyl, optionally substituted    aralkynyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted cycloalkylalkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl;    as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof.

In another aspect, this invention is directed to pharmaceuticalcompositions comprising a pharmaceutically acceptable excipient and atherapeutically effective amount of a compound of formula (Ia), acompound of formula (Ib), a compound of formula (Ic) or a compound offormula (Ib), as described above, as an isolated stereoisomer or mixturethereof, or as a pharmaceutically acceptable salt thereof.

In another aspect, this invention is directed to methods of treating adisease or condition associated with Axl activity in a mammal, whereinthe methods comprise administering to the mammal a therapeuticallyeffective amount of a compound of formula (Ia), a compound of formula(Ib), a compound of formula (Ic) or a compound of formula (Ib), asdescribed above, as an isolated stereoisomer or mixture thereof, or apharmaceutically acceptable salt thereof, or a therapeutically effectiveamount of a pharmaceutical composition comprising a pharmaceuticallyacceptable excipient and a therapeutically effective amount of acompound of formula (Ia), a compound of formula (Ib), a compound offormula (Ic) or a compound of formula (Ib), as described above, as anisolated stereoisomer or mixture thereof, or a pharmaceuticallyacceptable salt thereof.

In another aspect, this invention provides assays to determine acompound of the invention effectiveness in inhibiting Axl activity in acell-based assay.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated:

“Amino” refers to the —NH₂ radical.

“Carboxy” refers to the —C(O)OH radical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Thioxo” refers to the ═S radical.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to twelve carbon atoms, preferably one toeight carbon atoms or one to six carbon atoms, and which is attached tothe rest of the molecule by a single bond, for example, methyl, ethyl,n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl,1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like.Unless stated otherwise specifically in the specification, an alkylradical may be optionally substituted by one or more of the followingsubstituents: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —OR²⁰,—OC(O)—R²⁰, —N(R²⁰)₂, —C(O)R²⁰, —C(O)OR²⁰, —C(O)N(R²⁰)₂,—N(R²⁰)C(O)OR²⁰, —N(R²⁰)C(O)R²⁰, —N(R²⁰)S(O)_(t)R²⁰ (where t is 1 or 2),—S(O)_(t)OR²⁰ (where t is 1 or 2), —S(O)_(p)R²⁰ (where p is 0, 1 or 2),and —S(O)_(t)N(R²⁰)₂ (where t is 1 or 2) where each R²⁰ is independentlyhydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocylylalkyl, heteroaryl or heteroarylalkyl.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing at least onedouble bond, having from two to twelve carbon atoms, preferably one toeight carbon atoms and which is attached to the rest of the molecule bya single bond, for example, ethenyl, prop-1-enyl, but-1-enyl,pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwisespecifically in the specification, an alkenyl radical may be optionallysubstituted by one or more of the following substituents: halo, cyano,nitro, oxo, thioxo, trimethylsilanyl, —OR²⁰, —OC(O)—R²⁰, —N(R²⁰)₂,—C(O)R²⁰, —C(O)OR²⁰, —C(O)N(R²⁰)₂, —N(R²⁰)C(O)OR²⁰, —N(R²⁰)C(O)R²⁰,—N(R²⁰)S(O)_(t)R²⁰ (where t is 1 or 2), —S(O)_(t)OR²⁰ (where t is 1 or2), —S(O)_(p)R²⁰ (where p is 0, 1 or 2), and —S(O)_(t)N(R²⁰)₂ (where tis 1 or 2) where each R²⁰ is independently hydrogen, alkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocylylalkyl, heteroaryl or heteroarylalkyl.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing at least onetriple bond, optionally containing at least one double bond, having fromtwo to twelve carbon atoms, preferably one to eight carbon atoms andwhich is attached to the rest of the molecule by a single bond, forexample, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.Unless stated otherwise specifically in the specification, an alkynylradical may be optionally substituted by one or more of the followingsubstituents: halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —OR²⁰,—OC(O)—R²⁰, —N(R²⁰)₂, —C(O)R²⁰, —C(O)OR²⁰, —C(O)N(R²⁰)₂,—N(R²⁰)C(O)OR²⁰, —N(R²⁰)C(O)R²⁰, —N(R²⁰)S(O)_(t)R²⁰ (where t is 1 or 2),—S(O)_(t)OR²⁰ (where t is 1 or 2), —S(O)_(p)R²⁰ (where p is 0, 1 or 2),and —S(O)_(t)N(R²⁰)₂ (where t is 1 or 2) where each R²⁰ is independentlyhydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocylylalkyl, heteroaryl or heteroarylalkyl.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, containing no unsaturation andhaving from one to twelve carbon atoms, for example, methylene,ethylene, propylene, n-butylene, and the like. The alkylene chain isattached to the rest of the molecule through a single bond and to theradical group through a single bond. The points of attachment of thealkylene chain to the rest of the molecule and to the radical group canbe through one carbon in the alkylene chain or through any two carbonswithin the chain. Unless stated otherwise specifically in thespecification, an alkylene chain may be optionally substituted by one ormore of the following substituents: halo, cyano, nitro, aryl,cycloalkyl, heterocyclyl, heteroaryl, oxo, thioxo, trimethylsilanyl,—OR²⁰, —OC(O)—R²⁰, —N(R²⁰)₂, —C(O)R²⁰, —C(O)OR²⁰, —C(O)N(R²⁰)₂,—N(R²⁰)C(O)OR²⁰, —N(R₂₀)C(O)R²⁰, —N(R²⁰)S(O)_(t)R²⁰ (where t is 1 or 2),—S(O)_(t)OR²⁰ (where t is 1 or 2), —S(O)_(p)R²⁰ (where p is 0, 1 or 2),and —S(O)_(t)N(R²⁰)₂ (where t is 1 or 2) where each R²⁰ is independentlyhydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocylylalkyl, heteroaryl or heteroarylalkyl.

“Alkenylene” or “alkenylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing at least onedouble bond and having from two to twelve carbon atoms, for example,ethenylene, propenylene, n-butenylene, and the like. The alkenylenechain is attached to the rest of the molecule through a double bond or asingle bond and to the radical group through a double bond or a singlebond. The points of attachment of the alkenylene chain to the rest ofthe molecule and to the radical group can be through one carbon or anytwo carbons within the chain. Unless stated otherwise specifically inthe specification, an alkenylene chain may be optionally substituted byone or more of the following substituents: halo, cyano, nitro, aryl,cycloalkyl, heterocyclyl, heteroaryl, oxo, thioxo, trimethylsilanyl,—OR²⁰, —OC(O)—R²⁰, —N(R²⁰)₂, —C(O)R²⁰, —C(O)OR²⁰, —C(O)N(R²⁰)₂,—N(R²⁰)C(O)OR²⁰, —N(R²⁰)C(O)R²⁰, —N(R²⁰)S(O)_(t)R²⁰ (where t is 1 or 2),—S(O)_(t)OR²⁰ (where t is 1 or 2), —S(O)_(p)R²⁰ (where p is 0, 1 or 2),and —S(O)_(t)N(R²⁰)₂ (where t is 1 or 2) where each R²⁰ is independentlyhydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocylylalkyl, heteroaryl or heteroarylalkyl.

“Alkynylene” or “alkynylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing at least onetriple bond and having from two to twelve carbon atoms, for example,propynylene, n-butynylene, and the like. The alkynylene chain isattached to the rest of the molecule through a single bond and to theradical group through a double bond or a single bond. The points ofattachment of the alkynylene chain to the rest of the molecule and tothe radical group can be through one carbon or any two carbons withinthe chain. Unless stated otherwise specifically in the specification, analkynylene chain may be optionally substituted by one or more of thefollowing substituents: alkyl, alkenyl, halo, haloalkenyl, cyano, nitro,aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, thioxo,trimethylsilanyl, —OR²⁰, —OC(O)—R²⁰, —N(R²⁰)₂, —C(O)R²⁰, —C(O)OR²⁰,—C(O)N(R²⁰)₂, —N(R²⁰)C(O)OR²⁰, —N(R²⁰)C(O)R²⁰, —N(R²⁰)S(O)_(t)R²⁰ (wheret is 1 or 2), —S(O)_(t)OR²⁰ (where t is 1 or 2), —S(O)_(p)R²⁰ (where pis 0, 1 or 2), and —S(O)_(t)N(R²⁰)₂ (where t is 1 or 2) where each R²⁰is independently hydrogen, alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocylylalkyl,heteroaryl or heteroarylalkyl.

“Alkoxy” refers to a radical of the formula —OR_(a) where R_(a) is analkyl radical as defined above containing one to twelve carbon atoms.The alkyl part of the alkoxy radical may be optionally substituted asdefined above for an alkyl radical.

“Alkoxyalkyl” refers to a radical of the formula —R_(b)—O—R_(a) whereR_(a) is an alkyl radical as defined above and R_(b) is an alkylenechain as defined above. The oxygen atom may be bonded to any carbon inthe alkyl radical or the alkylene chain. The alkyl part of thealkoxyalkyl radical may be optionally substituted as defined above foran alkyl radical and the alkylene chain part of the alkoxyalkyl radicalmay be optionally substituted as defined above for an alkylene chain.

“Aryl” refers to a hydrocarbon ring system radical comprising hydrogen,6 to 14 carbon atoms and at least one aromatic ring. For purposes ofthis invention, the aryl radical may be a monocyclic, bicyclic, ortricyclic ring system, which may included spiro ring systems. An arylradical is commonly, but not necessarily, attached to the parentmolecule via an aromatic ring of the aryl radical. For purposes of thisinvention, an “aryl” radical as defined herein can not contain ringshaving more than 7 members and cannot contain rings wherein twonon-adjacent members thereof are connected by a direct bond or throughan atom or a group of atoms (i.e., a bridged ring system). Aryl radicalsinclude, but are not limited to, aryl radicals derived fromacenaphthylene, anthracene, azulene, benzene,6,7,8,9-tetrahydro-5H-benzo[7]annulene, fluorene, as-indacene,s-indacene, indane, indene, naphthalene, phenalene, and phenanthrene.Unless stated otherwise specifically in the specification, the term“optionally substituted aryl” is meant to include aryl radicalsoptionally substituted by one or more substituents independentlyselected from the group consisting of alkyl, alkenyl, alkynyl, halo,haloalkyl, haloalkenyl, haloalkynyl, cyano, nitro, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedaralkenyl, optionally substituted aralkynyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heterocyclylalkenyl,optionally substituted heterocyclylalkynyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, optionallysubstituted heteroarylalkenyl, optionally substituted heteroarylalkynyl,—R²¹—OR²⁰, —R²¹—OC(O)—R²⁰, —R²¹—N(R²⁰)₂, —R²¹—C(O)R²⁰, —R²¹—C(O)OR²⁰,—R²¹—C(O)N(R²⁰)₂, —R²¹—O—R²²—C(O)N(R²⁰)₂, —R²¹N(R²⁰)C(O)OR²⁰,—R²¹—N(R²⁰)C(O)R²⁰, —N(R²⁰)C(O)R²⁰, —R²¹—N(R²⁰)S(O)_(t)R²⁰ (where t is 1or 2), —R²¹—S(O)_(t)OR²⁰ (where t is 1 or 2), —R²¹—S(O)_(p)R²⁰ (where pis 0, 1 or 2), and —R²¹—S(O)_(t)N(R²)₂ (where t is 1 or 2), where eachR²⁰ is independently selected from the group consisting of hydrogen,alkyl, haloalkyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl andoptionally substituted heteroarylalkyl, or two R²⁰'s, together with thecommon nitrogen to which they are both attached, may optionally form anoptionally substituted N-heterocyclyl or an optionally substitutedN-heteroaryl, each R²¹ is independently a direct bond or a straight orbranched alkylene or alkenylene chain, and R²² is a straight or branchedalkylene or alkenylene chain.

“Aralkyl” refers to a radical of the formula —R_(b)—R_(c) where R_(b) isan alkylene chain as defined above and R_(c) is one or more arylradicals as defined above, for example, benzyl, diphenylmethyl and thelike. The alkylene chain part of the aralkyl radical may be optionallysubstituted as described above for an alkylene chain. The aryl part ofthe aralkyl radical may be optionally substituted as described above foran aryl.

“Aralkenyl” refers to a radical of the formula —R_(d)—R_(c) where R_(d)is an alkenylene chain as defined above and R_(c) is one or more arylradicals as defined above. The aryl part of the aralkenyl radical may beoptionally substituted as described above for an aryl. The alkenylenechain part of the aralkenyl radical may be optionally substituted asdefined above for an alkenylene group.

“Aralkynyl” refers to a radical of the formula —R_(e)R_(c), where R_(e)is an alkynylene chain as defined above and R_(c) is one or more arylradicals as defined above. The aryl part of the aralkynyl radical may beoptionally substituted as described above for an aryl. The alkynylenechain part of the aralkynyl radical may be optionally substituted asdefined above for an alkynylene chain.

“Aryloxy” refers to a radical of the formula —OR_(c), where R_(c) is anaryl as defined above. The aryl part of the aryloxy radical may beoptionally substituted as defined above.

“Aralkyloxy” refers to a radical of the formula —OR_(f) where R_(f) isan aralkyl radical as defined above. The aralkyl part of the aralkyloxyradical may be optionally substituted as defined above.

“Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which may include fused or bridged ring systems, having from three tofifteen carbon atoms, preferably having from three to ten carbon atoms,more preferably from five to seven carbons and which is saturated orunsaturated and attached to the rest of the molecule by a single bond.Monocyclic radicals include, for example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclicradicals include, for example, C₁₀ radicals such as adamantanyl anddecalinyl, and C₇ radicals such as norbornanyl, norbornenyl, as well assubstituted polycyclic radicals for example substituted C₇ radicals suchas 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwisestated specifically in the specification, the term “optionallysubstituted cycloalkyl” is meant to include cycloalkyl radicals whichare optionally substituted by one or more substituents independentlyselected from the group consisting of alkyl, alkenyl, alkynyl, halo,haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted aralkenyl, optionally substituted aralkynyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted cycloalkylalkenyl, optionally substitutedcycloalkylalkynyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substitutedheterocyclylalkenyl, optionally substituted heterocyclylalkynyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heteroarylalkenyl, optionallysubstituted heteroarylalkynyl, —R²¹—OR²⁰, —R²¹—OC(O)—R²⁰, —R²¹—N(R²⁰)₂,—R²¹—C(O)R²⁰, —R²¹—C(O)OR²⁰, —R²¹—C(O)N(R²⁰)₂, —R²¹—N(R²⁰)C(O)OR²⁰,—R²¹—N(R²⁰)C(O)R²⁰, —R²¹—N(R²⁰)S(O)_(t)R²⁰ (where t is 1 or 2),—R²¹—S(O)_(t)OR²⁰ (where t is 1 or 2), —R²¹—S(O)_(p)R²⁰ (where p is 0, 1or 2), and —R²¹—S(O)_(t)N(R²⁰)₂ (where t is 1 or 2), where each R²⁰ isindependently selected from the group consisting of hydrogen, alkyl,haloalkyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl and optionallysubstituted heteroarylalkyl, or two R²⁰'s, together with the commonnitrogen to which they are both attached, may optionally form anoptionally substituted N-heterocyclyl or an optionally substitutedN-heteroaryl, and each R²¹ is independently a direct bond or a straightor branched alkylene or alkenylene chain.

“Cycloalkylalkyl” refers to a radical of the formula —R_(b)R_(g) whereR_(b) is an alkylene chain as defined above and R_(g) is a cycloalkylradical as defined above. The alkylene chain and the cycloalkyl radicalmay be optionally substituted as defined above.

“Cycloalkylalkenyl” refers to a radical of the formula —R_(d)R_(g) whereR_(d) is an alkenylene chain as defined above and R_(g) is a cycloalkylradical as defined above. The alkenylene chain and the cycloalkylradical may be optionally substituted as defined above.

“Cycloalkylalkynyl” refers to a radical of the formula —R_(e)R_(g) whereR_(e) is an alkynylene radical as defined above and R_(g) is acycloalkyl radical as defined above. The alkynylene chain and thecycloalkyl radical may be optionally substituted as defined above.

“Halo” refers to bromo, chloro, fluoro or iodo.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, for example,trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl,1-bromomethyl-2-bromoethyl, and the like. The alkyl part of thehaloalkyl radical may be optionally substituted as defined above for analkyl radical.

“Haloalkoxy” refers to an alkoxy radical, as defined above, that issubstituted by one or more halo radicals, as defined above, for example,trifluoromethoxy, difluoromethoxy, trichloromethoxy,2,2,2-trifluoroethoxy, and the like. The alkoxy part of the haloalkoxyradical may be optionally substituted as defined above for an alkoxyradical.

“Haloalkenyl” refers to an alkenyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above. The alkenylpart of the haloalkyl radical may be optionally substituted as definedabove for an alkenyl radical.

“Haloalkynyl” refers to an alkynyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above. The alkynylpart of the haloalkyl radical may be optionally substituted as definedabove for an alkynyl radical.

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ringradical which comprises one to twelve carbon atoms and from one to sixheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur. Unless stated otherwise specifically in the specification, theheterocyclyl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include spiro, fused or bridged ringsystems; and the nitrogen, carbon or sulfur atoms in the heterocyclylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized; and the heterocyclyl radical may be partially or fullysaturated. Examples of such heterocyclyl radicals include, but are notlimited to, dioxolanyl, 1,4-diazepanyl, decahydroisoquinolyl,imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl,octahydro-1H-pyrrolo[3,2-c]pyridinyl,octahydro-1H-pyrrolo[2,3-c]pyridinyl,octahydro-1H-pyrrolo[2,3-b]pyridinyl,octahydro-1H-pyrrolo[3,4-b]pyridinyl, octahydropyrrolo[3,4-c]pyrrolyl,octahydro-1H-pyrido[1,2-a]pyrazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl,4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, thienyl[1,3]dithianyl, trithianyl,tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, azetidinyl,octahydropyrrolo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-b]pyrrolyl,decahydroprazino[1,2-a]azepinyl, azepanyl, azabicyclo[3.2.1]octyl, and2,7-diazaspiro[4.4]nonanyl. Unless stated otherwise specifically in thespecification, the term “optionally substituted heterocyclyl” is meantto include heterocyclyl radicals as defined above which are optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl,haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,optionally substituted aralkyl, optionally substituted aralkenyl,optionally substituted aralkynyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedcycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted heterocyclylalkenyl, optionally substitutedheterocyclylalkynyl, optionally substituted heteroaryl, optionallysubstituted heteroarylalkyl, optionally substituted heteroarylalkenyl,optionally substituted heteroarylalkynyl, —R²¹—OR²⁰, —R²¹—OC(O)—R²⁰,—R²¹—N(R²⁰)₂, —R²¹—C(O)R²⁰, —R²¹—C(O)OR²⁰, —R²¹—C(O)N(R²⁰)₂,—R²¹—N(R²⁰)C(O)OR²⁰, —R²¹—N(R²⁰)C(O)R²⁰, —R²¹—N(R²⁰)S(O)_(t)R²⁰ (where tis 1 or 2), —R²¹—S(O)_(t)OR²⁰ (where t is 1 or 2), —R²¹—S(O)_(p)R²⁰(where p is 0, 1 or 2), and —R²¹—S(O)_(t)N(R²⁰)₂ (where t is 1 or 2),where each R²⁰ is independently selected from the group consisting ofhydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl and optionally substituted heteroarylalkyl, or two R²⁰'s,together with the common nitrogen to which they are both attached, mayoptionally form an optionally substituted N-heterocyclyl or anoptionally substituted N-heteroaryl, and each R²¹ is independently adirect bond or a straight or branched alkylene or alkenylene chain.

“N-heterocyclyl” refers to a heterocyclyl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heterocyclyl radical to the rest of the molecule is through anitrogen atom in the heterocyclyl radical. An N-heterocyclyl radical maybe optionally substituted as described above for heterocyclyl radicals.

“Heterocyclylalkyl” refers to a radical of the formula —R_(b)R_(h) whereR_(b) is an alkylene chain as defined above and R_(h) is a heterocyclylradical as defined above, and if the heterocyclyl is anitrogen-containing heterocyclyl, the heterocyclyl may be attached tothe alkyl radical at the nitrogen atom. The alkylene chain of theheterocyclylalkyl radical may be optionally substituted as defined abovefor an alkyene chain. The heterocyclyl part of the heterocyclylalkylradical may be optionally substituted as defined above for aheterocyclyl radical.

“Heterocyclylalkenyl” refers to a radical of the formula —R_(d)R_(h)where R_(d) is an alkenylene chain as defined above and R_(h) is aheterocyclyl radical as defined above, and if the heterocyclyl is anitrogen-containing heterocyclyl, the heterocyclyl may be attached tothe alkenylene chain at the nitrogen atom. The alkenylene chain of theheterocyclylalkenyl radical may be optionally substituted as definedabove for an alkenylene chain. The heterocyclyl part of theheterocyclylalkenyl radical may be optionally substituted as definedabove for a heterocyclyl radical.

“Heterocyclylalkynyl” refers to a radical of the formula —R_(e)R_(h)where R_(e) is an alkynylene chain as defined above and R_(h) is aheterocyclyl radical as defined above, and if the heterocyclyl is anitrogen-containing heterocyclyl, the heterocyclyl may be attached tothe alkynyl radical at the nitrogen atom. The alkynylene chain part ofthe heterocyclylalkynyl radical may be optionally substituted as definedabove for an alkynylene chain. The heterocyclyl part of theheterocyclylalkynyl radical may be optionally substituted as definedabove for a heterocyclyl radical.

“Heteroaryl” refers to a 5- to 14-membered ring system radicalcomprising hydrogen atoms, one to thirteen carbon atoms, one to sixheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur, and at least one aromatic ring. A heteroaryl radical iscommonly, but not necessarily, attached to the parent molecule via anaromatic ring of the heteroaryl radical. For purposes of this invention,the heteroaryl radical may be a monocyclic, bicyclic or tricyclic ringsystem, which may include spiro ring systems; and the nitrogen, carbonor sulfur atoms in the heteroaryl radical may be optionally oxidized;the nitrogen atom may be optionally quaternized. For purposes of thisinvention, the aromatic ring of the heteroaryl radical need not containa heteroatom, as long as one ring of the heteroaryl radical contains aheteroatom. For example, 1,2,3,4-tetrahydroisoquinolin-7-yl isconsidered a “heteroaryl” for the purposes of this invention. Forpurposes of this invention, a “heteroaryl” radical as defined herein cannot contain rings having more than 7 members or rings wherein twonon-adjacent members thereof are connected by a direct bond or throughan atom or a group of atoms (i.e., a bridged ring system). Examples ofheteroaryl radicals include, but are not limited to, azepinyl,acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl,benzooxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,7′,8′-dihydro-5′H-spiro[[1,3]dioxolane-2,6′-quinoline]-3′-yl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl,3,4-dihydro-2H-benzo[b][1,4]oxazinyl, dibenzofuranyl, dibenzothiophenyl,furanyl, furanonyl, furo[3,2-c]pyridinyl, imidazolyl, indazolyl,indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl,indolizinyl, isoxazolyl, naphthyridinyl, 1,6-naphthyridinonyl,oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, phenanthridinyl,pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl,pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl,pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl,2,3,4,5-tetrahydrobenzo[b]oxepinyl,3,4-dihydro-2H-benzo[b][1,4]dioxepinyl,6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridinyl,6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,triazolyl, tetrazolyl, 1,2,3,4-tetrahydroisoquinolin-7-yl, triazinyl,thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl,thieno[2,3-c]pyridinyl, and thiophenyl (i.e. thienyl). Unless statedotherwise specifically in the specification, the term “optionallysubstituted heteroaryl” is meant to include heteroaryl radicals asdefined above which are optionally substituted by one or moresubstituents selected from the group consisting of alkyl, alkenyl,alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano,nitro, optionally substituted aryl, optionally substituted aralkyl,optionally substituted aralkenyl, optionally substituted aralkynyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionallysubstituted cycloalkylalkynyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheterocyclylalkenyl, optionally substituted heterocyclylalkynyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heteroarylalkenyl, optionallysubstituted heteroarylalkynyl, —R²¹—OR²⁰, —R²¹—OC(O)—R²⁰, —R²¹—N(R²⁰)₂,—R²¹—C(O)R²⁰, —R²¹—C(O)OR²⁰, —R²¹—C(O)N(R²⁰)₂, —R²¹—N(R²⁰)C(O)OR²⁰,—R²¹—N(R²⁰)C(O)R²⁰, —R²¹—N(R²⁰)S(O)_(t)R²⁰ (where t is 1 or 2),—R²¹—S(O)_(t)OR²⁰ (where t is 1 or 2), —R²¹—S(O)_(p)R²⁰ (where p is 0, 1or 2), and —R²¹—S(O)_(t)N(R²⁰)₂ (where t is 1 or 2), where each R²⁰ isindependently selected from the group consisting of hydrogen, alkyl,haloalkyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl and optionallysubstituted heteroarylalkyl, or two R²⁰'s, together with the commonnitrogen to which they are both attached, may optionally form anoptionally substituted N-heterocyclyl or an optionally substitutedN-heteroaryl, and each R²¹ is independently a direct bond or a straightor branched alkylene or alkenylene chain.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. An N-heteroaryl radical may beoptionally substituted as described above for heteroaryl radicals.

“Heteroarylalkyl” refers to a radical of the formula —R_(b)R_(i) whereR_(b) is an alkylene chain as defined above and R_(i) is a heteroarylradical as defined above. The heteroaryl part of the heteroarylalkylradical may be optionally substituted as defined above for a heteroaryl.The alkylene chain part of the heteroarylalkyl radical may be optionallysubstituted as defined above for an alkylene chain.

“Heteroarylalkenyl” refers to a radical of the formula —R_(d)R_(i) whereR_(d) is an alkenylene chain as defined above and R_(i) is a heteroarylradical as defined above. The heteroaryl part of the heteroarylalkenylradical may be optionally substituted as defined above for a heteroaryl.The alkenylene chain part of the heteroarylalkenyl radical may beoptionally substituted as defined above for an alkenylene chain.

“Heteroarylalkynyl” refers to a radical of the formula —R_(e)R_(i) whereR_(e) is an alkynylene chain as defined above and R_(i) is a heteroarylradical as defined above. The heteroaryl part of the heteroarylalkynylradical may be optionally substituted as defined above for a heteroaryl.The alkynylene chain part of the heteroarylalkynyl radical may beoptionally substituted as defined above for an alkynylene chain.

“Hydroxyalkyl” refers to an alkyl radical as defined above which issubstituted by one or more hydroxy radicals (—OH).

“Hydroxyalkenyl” refers to an alkenyl radical as defined above which issubstituted by one or more hydroxy radicals (—OH).

“Hydroxyalkenyl” refers to an alkynyl radical as defined above which issubstituted by one or more hydroxy radicals (—OH).

Certain chemical groups named herein may be preceded by a shorthandnotation indicating the total number of carbon atoms that are to befound in the indicated chemical group. For example; C₇-C₁₂alkyldescribes an alkyl group, as defined below, having a total of 7 to 12carbon atoms, and C₄-C₁₂cycloalkylalkyl describes a cycloalkylalkylgroup, as defined below, having a total of 4 to 12 carbon atoms. Thetotal number of carbons in the shorthand notation does not includecarbons that may exist in substituents of the group described.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

“Mammal” includes humans and domestic animals, such as cats, dogs,swine, cattle, sheep, goats, horses, rabbits, and the like. Preferably,for purposes of this invention, the mammal is a human.

“Optional” or “optionally” means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution. When a functional group is described as “optionallysubstituted,” and in turn, substitutents on the functional group arealso “optionally substituted” and so on, for the purposes of thisinvention, such iterations are limited to five.

“Pharmaceutically acceptable excipient” includes without limitation anyadjuvant, carrier, excipient, glidant, sweetening agent, diluent,preservative, dye/colorant, flavor enhancer, surfactant, wetting agent,dispersing agent, suspending agent, stabilizer, isotonic agent, solvent,or emulsifier which has been approved by the United States Food and DrugAdministration as being acceptable for use in humans or domesticanimals.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as, but not limited to,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, and organic acids such as, but not limitedto, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid,ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid,citric acid, cyclamic acid, dodecylsulfonic acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuricacid, isobutyric acid, lactic acid, lactobionic acid, lauric acid,maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonicacid, mucic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid,4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroaceticacid, undecylenic acid, and the like.

“Pharmaceutically acceptable base addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Salts derived from inorganic bases include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as ammonia,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, diethanolamine, ethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, procaine, hydrabamine, choline, betaine, benethamine,benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine,triethanolamine, tromethamine, purines, piperazine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particularly preferredorganic bases are isopropylamine, diethylamine, ethanolamine,trimethylamine, dicyclohexylamine, choline and caffeine.

A “pharmaceutical composition” refers to a formulation of a compound ofthe invention and a medium generally accepted in the art for thedelivery of the biologically active compound to mammals, for example,humans. Such a medium includes all pharmaceutically acceptable carriers,diluents or excipients therefor.

“Therapeutically effective amount” refers to that amount of a compoundof the invention which, when administered to a mammal, preferably ahuman, is sufficient to effect treatment, as defined below, of a diseaseor condition of interest in the mammal, preferably a human. The amountof a compound of the invention which constitutes a “therapeuticallyeffective amount” will vary depending on the compound, the disease orcondition and its severity, and the age of the mammal to be treated, butcan be determined routinely by one of ordinary skill in the art havingregard to his own knowledge and to this disclosure.

“Treating” or “treatment” as used herein covers the treatment of thedisease or condition of interest in a mammal, preferably a human, havingthe disease or condition of interest, and includes:

(i) preventing the disease or condition from occurring in a mammal, inparticular, when such mammal is predisposed to the condition but has notyet been diagnosed as having it;

(ii) inhibiting the disease or condition, i.e., arresting itsdevelopment;

(iii) relieving the disease or condition, i.e., causing regression ofthe disease or condition; or

(iv) stabilizing the disease or condition.

As used herein, the terms “disease” and “condition” may be usedinterchangeably or may be different in that the particular malady orcondition may not have a known causative agent (so that etiology has notyet been worked out) and it is therefore not yet recognized as a diseasebut only as an undesirable condition or syndrome, wherein a more or lessspecific set of symptoms have been identified by clinicians.

The compounds of the invention, or their pharmaceutically acceptablesalts may contain one or more asymmetric centres and may thus give riseto enantiomers, diastereomers, and other stereoisomeric forms that maybe defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as(D)- or (L)- for amino acids. The present invention is meant to includeall such possible isomers, as well as their racemic and optically pureforms. Optically active (+) and (−), (R)- and (S)-, or (D)- and(L)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques, such as HPLC using a chiralcolumn. When the compounds described herein contain olefinic doublebonds or other centres of geometric asymmetry, and unless specifiedotherwise, it is intended that the compounds include both E and Zgeometric isomers. Likewise, all tautomeric forms are also intended tobe included.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present invention contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are nonsuperimposeablemirror images of one another.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The present invention includestautomers of any said compounds.

“Atropisomers” are stereoisomers resulting from hindered rotation aboutsingle bonds where the barrier to rotation is high enough to allow forthe isolation of the conformers (Eliel, E. L.; Wilen, S. H.Stereochemistry of Organic Compounds; Wiley & Sons: New York, 1994;Chapter 14). Atropisomerism is significant because it introduces anelement of chirality in the absence of stereogenic atoms. The inventionis meant to encompass atropisomers, for example in cases of limitedrotation around the single bonds emanating from the core triazolestructure, atropisomers are also possible and are also specificallyincluded in the compounds and/or prodrugs of the invention.

The chemical naming protocol and structure diagrams used herein are amodified form of the I.U.P.A.C. nomenclature system wherein thecompounds of the invention are named herein as derivatives of thecentral core structure, i.e., the triazole structure. For complexchemical names employed herein, a substituent group is named before thegroup to which it attaches. For example, cyclopropylethyl comprises anethyl backbone with cyclopropyl substituent. In chemical structurediagrams, all bonds are identified, except for some carbon atoms, whichare assumed to be bonded to sufficient hydrogen atoms to complete thevalency.

For example, the following compound of formula (Ia)

is named herein as(1R,2R,3S,5R)-2-(5-chloro-2-(4-(4-cyclohexylpiperazine-1-carbonyl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide.

Embodiments of the Invention

Of the various aspects of the invention set forth above in the Summaryof the Invention, certain embodiments of the compounds of formula (Ia),as set forth above in the Summary of the Invention, are preferred.

One embodiment of a compound of formula (Ia) is a compound of formula(Ia)

wherein:

-   n is 0 to 4;-   m is 0 to 1;-   R¹, R², R⁴ and R⁵ are each independently hydrogen, alkyl,    cycloalkylalkyl, —R¹⁴—OR¹⁵, —C(O)R¹⁵ or —C(O)N(R¹¹)R¹²;-   R^(3a), R^(3b), R^(3c), R^(3d) and R^(3e) are each independently    selected from the group consisting of hydrogen, alkyl, halo,    haloalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl,    optionally substituted heteroarylalkyl, —R¹⁷—OR¹⁶, —R¹⁷—N(R¹⁶)₂,    —R¹⁷—C(O)R¹⁶, —R¹⁷—C(O)OR¹⁶, —R¹⁷—C(O)N(R¹⁶)₂,    —R¹⁷—O—R¹⁸—C(O)N(R¹⁶)₂, —R¹⁷—O—R¹⁸—N(R¹⁶)₂, and —R¹⁷—S(O)_(t)N(R¹⁶)₂    (where t is 1 or 2), where each R¹⁶ is independently hydrogen,    alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted heterocyclyl, optionally substituted heterocyclylalkyl,    optionally substituted heteroaryl or optionally substituted    heteroarylalkyl, each R¹⁷ is independently a direct bond or a    straight or branched alkylene or alkenylene chain, and R¹⁸ is a    straight or branched alkylene or alkenylene chain;-   R⁶, R⁷ and R⁸ are each independently alkyl, haloalkyl, or —R¹³—OR¹⁵;-   each R⁹ and R¹⁰ is independently alkyl, halo, haloalkyl, aryl or    aralkyl;-   R¹¹ and R¹² are each independently selected from the group    consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, —R¹⁴—OR¹⁵, —R¹⁴—CN, —R¹⁴—NO₂,    —R¹⁴—N(R¹⁵)₂, —R¹⁴—C(O)OR¹⁵ and —R¹⁴—C(O)N(R¹⁵)₂;-   R¹³ is independently selected from the group consisting of a direct    bond or an optionally substituted straight or branched alkylene    chain;-   each R¹⁴ is an optionally substituted straight or branched alkylene    chain; and-   each R¹⁵ is independently selected from the group consisting of    hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted cycloalkyl, optionally    substituted cycloalkylalkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, optionally substituted    heteroaryl, and optionally substituted heteroarylalkyl.

Another embodiment of a compound of formula (Ia) is a compound offormula (Ia)

wherein:

-   n is 0;-   m is 0 to 1,-   R¹, R², R⁴ and R⁵ are each independently hydrogen, alkyl,    cycloalkylalkyl, or —R¹⁴—OR¹⁵;-   R^(3a), R^(3b), R^(3c), R^(3d) and R^(3e) are each independently    selected from the group consisting of hydrogen, alkyl, halo,    haloalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl,    optionally substituted heteroarylalkyl, —R¹⁷—OR¹⁶, —R¹⁷—N(R¹⁶)₂,    —R¹⁷—C(O)R¹⁶, —R¹⁷—C(O)OR¹⁶, —R¹⁷—C(O)N(R¹⁶)₂,    —R¹⁷—O—R¹⁸—C(O)N(R¹⁶)₂, —R¹⁷—O—R¹⁸—N(R¹⁶)₂, and —R¹⁷—S(O)_(t)N(R¹⁶)₂    (where t is 1 or 2), where each R¹⁶ is independently hydrogen,    alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted heterocyclyl, optionally substituted heterocyclylalkyl,    optionally substituted heteroaryl or optionally substituted    heteroarylalkyl, each R¹⁷ is independently a direct bond or a    straight or branched alkylene or alkenylene chain, and R¹⁸ is a    straight or branched alkylene or alkenylene chain;-   R⁶, R⁷ and R⁸ are each independently alkyl, haloalkyl, or —R¹³—OR¹⁵;-   R¹⁰ is alkyl, halo or haloalkyl;-   R¹³ is selected from the group consisting of a direct bond or an    optionally substituted straight or branched alkylene chain;-   R¹⁴ is an optionally substituted straight or branched alkylene    chain; and-   R¹⁵ is selected from the group consisting of hydrogen, alkyl,    haloalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl,    and optionally substituted heteroarylalkyl.

Another embodiment of a compound of formula (Ia) is a compound offormula (Ia)

wherein:

-   n is 0;-   m is 0 to 1;-   R¹, R², R⁴ and R⁵ are each independently hydrogen, alkyl,    cycloalkylalkyl, or —R¹⁴—OR¹⁵;-   R^(3a), R^(3b), R^(3c), R^(3d) and R^(3e) are each independently    selected from the group consisting of hydrogen, alkyl, halo,    haloalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl, or    optionally substituted heteroarylalkyl;-   R⁶, R⁷ and R⁸ are each independently alkyl, haloalkyl, or —R¹³—OR¹⁵;-   R¹⁰ is alkyl, halo or haloalkyl;-   R¹³ is selected from the group consisting of a direct bond or an    optionally substituted straight or branched alkylene chain;-   R¹⁴ is an optionally substituted straight or branched alkylene    chain; and-   R¹⁵ is selected from the group consisting of hydrogen, alkyl,    haloalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl,    and optionally substituted heteroarylalkyl.

Another embodiment of a compound of formula (Ia) is a compound offormula (Ia)

wherein:

-   n is 0;-   m is 0 to 1;-   R¹, R², R⁴ and R⁵ are each independently hydrogen, alkyl,    cycloalkylalkyl, or —R¹⁴—OR¹⁵;-   R^(3a), R^(3b), and R^(3e) are each hydrogen;-   R^(3c) and R^(3d) are each independently selected from the group    consisting of hydrogen, alkyl, halo, haloalkyl, optionally    substituted heterocyclyl, optionally substituted heterocyclylalkyl,    optionally substituted heteroaryl, or optionally substituted    heteroarylalkyl;-   R⁶, R⁷ and R⁸ are each independently alkyl, haloalkyl, or —R¹³—OR¹⁵;-   R¹⁰ is alkyl, halo or haloalkyl;-   R¹³ is selected from the group consisting of a direct bond or an    optionally substituted straight or branched alkylene chain;-   R¹⁴ is an optionally substituted straight or branched alkylene    chain; and-   R¹⁵ is selected from the group consisting of hydrogen, alkyl,    haloalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl,    and optionally substituted heteroarylalkyl.

Another embodiment of a compound of formula (Ia) is a compound offormula (Ia) selected from the group consisting of:

-   (1R,2R,3S,5R)-2-(5-chloro-2-(4-morpholinophenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-chloro-2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-chloro-2-(3-chloro-4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-chloro-2-(4-(pyridin-4-ylmethyl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-chloro-2-(4-(4-(4-fluorophenyl)piperazin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-chloro-2-(4-(1-methylpiperidin-4-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(2-(4-(4-acetylpiperazin-1-yl)phenylamino)-5-chloropyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-chloro-2-(4-chloro-3-(4-ethylpiperazin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(2-(3-(4-acetylpiperazin-1-yl)-4-chlorophenylamino)-5-chloropyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(2-(benzyloxy)ethyl)-2-(5-chloro-2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-ylamino)-6,6-dimethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(2-(3-(4-(methoxycarbonyl)piperazin-1-yl)-4-chlorophenylamino)-5-chloropyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-ylamino)-2-(2-hydroxyethyl)-6,6-dimethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-chloro-2-(3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-chloro-2-(3-fluoro-4-(4-(diethylamino)piperidin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-fluoro-2-(3-chloro-4-(4,4-difluoropiperidin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-fluoro-2-(3-fluoro-4-(4,4-difluoropiperidin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-fluoro-2-(3-chloro-4-(4-methylsulfonylpiperazin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-fluoro-2-(3-trifluoromethyl-4-(4-methylsulfonylpiperazin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-fluoro-2-(3-chloro-4-(4-acetylpiperazin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-fluoro-2-(3-trifluoromethyl-4-(4-acetylpiperazin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-chloro-2-(4-(4-(2-hydroxyethyl)piperazin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-methyl-2-(4-(4-(2-hydroxyethyl)piperazin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-methyl-2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-methyl-2-(3-fluoro-4-(4,4-difluoropiperidin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-trifluoromethyl-2-(3-fluoro-4-(4-(diethylamino)piperidin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-chloro-2-(3-fluoro-4-(4-(4-methylpiperidin-1-yl)piperidin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-fluoro-2-(3-fluoro-4-(4-(4-methylpiperidin-1-yl)piperidin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;    and-   (1R,2R,3S,5R)-2-(5-chloro-2-(3-fluoro-4-(4-(diethylamino)piperidin-1-yl)phenylamino)pyrimidin-4-ylamino)-N-cyclopropyl-2,6,6-trimethylbicyclo[3.1.1]heptane-3-carboxamide.

Another embodiment of a compound of formula (Ia) is a compound offormula (Ia)

wherein:

-   n is 0;-   m is 0 to 1;-   R¹, R², R⁴ and R⁵ are each independently hydrogen, alkyl,    cycloalkylalkyl, or —R¹⁴—OR¹⁵;-   R^(3a), R^(3b), R^(3c), R^(3d) and R^(3e) are each independently    selected from the group consisting of hydrogen, alkyl, halo,    haloalkyl, —R¹⁷—OR¹⁶, —R¹⁷—N(R¹⁶)₂, —R¹⁷—C(O)R¹⁶, —R¹⁷—C(O)OR¹⁶,    —R¹⁷—C(O)N(R¹⁶)₂, —R¹⁷—O—R¹⁸—C(O)N(R¹⁶)₂, —R¹⁷—O—R¹⁸—N(R¹⁶)₂, and    —R¹⁷—S(O)_(t)N(R¹⁶)₂ (where t is 1 or 2), where each R¹⁶ is    independently hydrogen, alkyl, haloalkyl, cycloalkyl,    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl or optionally    substituted heteroarylalkyl, each R¹⁷ is independently a direct bond    or a straight or branched alkylene or alkenylene chain, and R¹⁸ is a    straight or branched alkylene or alkenylene chain;-   R⁶, R⁷ and R⁸ are each independently alkyl, haloalkyl, or —R¹³—OR¹⁵;-   R¹⁰ is alkyl, halo or haloalkyl;-   R¹³ is selected from the group consisting of a direct bond or an    optionally substituted straight or branched alkylene chain;-   R¹⁴ is an optionally substituted straight or branched alkylene    chain; and-   R¹⁵ is selected from the group consisting of hydrogen, alkyl,    haloalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl,    and optionally substituted heteroarylalkyl.

Another embodiment of a compound of formula (Ia) is a compound offormula (Ia)

wherein:

-   n is 0;-   m is 0 to 1;-   R¹, R², R⁴ and R⁵ are each independently hydrogen, alkyl,    cycloalkylalkyl, or —R¹⁴—OR¹⁵;-   R^(3a), R^(3b) and R^(3e) are each hydrogen;-   R^(3c) and R^(3d) are each independently selected from the group    consisting of hydrogen, alkyl, halo, haloalkyl, —R¹⁷—OR¹⁶,    —R¹⁷—N(R¹⁶)₂, —R¹⁷—C(O)R¹⁶, —R¹⁷—C(O)OR¹⁶, —R¹⁷—C(O)N(R¹⁶)₂,    —R¹⁷—O—R¹⁸—C(O)N(R¹⁶)₂, —R¹⁷—O—R¹⁸—N(R¹⁶)₂, and —R¹⁷—S(O)_(t)N(R¹⁶)₂    (where t is 1 or 2), where each R¹⁶ is independently hydrogen,    alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted heterocyclyl, optionally substituted heterocyclylalkyl,    optionally substituted heteroaryl or optionally substituted    heteroarylalkyl, each R¹⁷ is independently a direct bond or a    straight or branched alkylene or alkenylene chain, and R¹⁸ is a    straight or branched alkylene or alkenylene chain;-   R⁶, R⁷ and R⁸ are each independently alkyl, haloalkyl, or —R¹³—OR¹⁵;-   R¹⁰ is alkyl, halo or haloalkyl;-   R¹³ is selected from the group consisting of a direct bond or an    optionally substituted straight or branched alkylene chain;-   R¹⁴ is an optionally substituted straight or branched alkylene    chain; and-   R¹⁵ is selected from the group consisting of hydrogen, alkyl,    haloalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl,    and optionally substituted heteroarylalkyl.

Another embodiment of a compound of formula (Ia) is a compound offormula (Ia) selected from the group consisting of:

-   (1R,2R,3S,5R)-2-(5-chloro-2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-chloro-2-(3-fluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-chloro-2-(3-sulfamoylphenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-chloro-2-(4-(2-methyl-2-(pyrrolidin-1-yl)propoxy)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-chloro-2-(4-(2-(cyclopentylamino)ethoxy)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-chloro-2-(4-(4-cyclohexylpiperazine-1-carbonyl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-chloro-2-(4-(4-methylpiperazine-1-carbonyl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-chloro-2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)pyrimidin-4-ylamino)-2,6,6-trimethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-chloro-2-(3-fluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)pyrimidin-4-ylamino)-2,6,6-trimethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-chloro-2-(4-(2-((cyclopentyl)(methyl)amino)ethoxy)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-fluoro-2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-chloro-2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)pyrimidin-4-ylamino)-N-cyclopropyl-2,6,6-trimethylbicyclo[3.1.1]heptane-3-carboxamide;    and-   (1R,2R,3S,5R)-2-(5-chloro-2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)pyrimidin-4-ylamino)-N-(1-methylethyl)-2,6,6-trimethylbicyclo[3.1.1]heptane-3-carboxamide.

Of the various aspects of the invention set forth above in the Summaryof the Invention, certain embodiments of the compounds of formula (Ib),as described above in the Summary of the Invention, are preferred.

One embodiment of a compound of formula (Ib) is a compound of formula(Ib)

wherein:

-   n is 0 to 4;-   m is 0 to 1;-   R¹, R², R⁴ and R⁵ are each independently hydrogen, alkyl,    cycloalkylalkyl, —R¹⁴—OR¹⁵, —C(O)R¹⁵ or —C(O)N(R¹¹)R¹²;-   R^(3a), R^(3b), R^(3c), R^(3d) and R^(3e) are each independently    selected from the group consisting of hydrogen, alkyl, halo,    haloalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl,    optionally substituted heteroarylalkyl, —R¹⁷—OR¹⁶, —R¹⁷—N(R¹⁶)₂,    —R¹⁷—C(O)R¹⁶, —R¹⁷—C(O)OR¹⁶, —R¹⁷—C(O)N(R¹⁶)₂,    —R¹⁷—O—R¹⁸—C(O)N(R¹⁶)₂, —R¹⁷—O—R¹⁸—N(R¹⁶)₂, and —R¹⁷—S(O)_(t)N(R¹⁶)₂    (where t is 1 or 2), where each R¹⁶ is independently hydrogen,    alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted heterocyclyl, optionally substituted heterocyclylalkyl,    optionally substituted heteroaryl or optionally substituted    heteroarylalkyl, each R¹⁷ is independently a direct bond or a    straight or branched alkylene or alkenylene chain, and R¹⁸ is a    straight or branched alkylene or alkenylene chain;-   R⁶, R⁷ and R⁸ are each independently alkyl, haloalkyl, or —R¹³—OR¹⁵;-   each R⁹ and R¹⁰ is independently alkyl, halo, haloalkyl, aryl or    aralkyl;-   R¹¹ and R¹² are each independently selected from the group    consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, —R¹⁴—OR¹⁵, —R¹⁴—CN, —R¹⁴—NO₂,    —R¹⁴—N(R¹⁵)₂, —R¹⁴—C(O)OR¹⁵ and —R¹⁴—C(O)N(R¹⁵)₂;-   R¹³ is independently selected from the group consisting of a direct    bond or an optionally substituted straight or branched alkylene    chain;-   each R¹⁴ is an optionally substituted straight or branched alkylene    chain; and-   each R¹⁵ is independently selected from the group consisting of    hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted cycloalkyl, optionally    substituted cycloalkylalkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, optionally substituted    heteroaryl, and optionally substituted heteroarylalkyl.

Another embodiment of a compound of formula (Ib) is a compound offormula (Ib)

wherein:

-   n is 0;-   m is 0 to 1;-   R¹, R², R⁴ and R⁵ are each independently hydrogen, alkyl,    cycloalkylalkyl, or —R¹⁴—OR¹⁵;-   R^(3a), R^(3b), R^(3c), R^(3d) and R^(3e) are each independently    selected from the group consisting of hydrogen, alkyl, halo,    haloalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl,    optionally substituted heteroarylalkyl, —R¹⁷—OR¹⁶, —R¹⁷—N(R¹⁶)₂,    —R¹⁷—C(O)R¹⁶, —R¹⁷—C(O)OR¹⁶, —R¹⁷—C(O)N(R¹⁶)₂,    —R¹⁷—O—R¹⁸—C(O)N(R¹⁶)₂, —R¹⁷—O—R¹⁸—N(R¹⁶)₂, and —R¹⁷—S(O)_(t)N(R¹⁶)₂    (where t is 1 or 2), where each R¹⁶ is independently hydrogen,    alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted heterocyclyl, optionally substituted heterocyclylalkyl,    optionally substituted heteroaryl or optionally substituted    heteroarylalkyl, each R¹⁷ is independently a direct bond or a    straight or branched alkylene or alkenylene chain, and R¹⁸ is a    straight or branched alkylene or alkenylene chain;-   R⁶, R⁷ and R⁸ are each independently alkyl, haloalkyl, or —R¹³—OR¹⁵;-   R¹⁰ is alkyl, halo or haloalkyl;-   R¹³ is selected from the group consisting of a direct bond or an    optionally substituted straight or branched alkylene chain;-   R¹⁴ is an optionally substituted straight or branched alkylene    chain; and-   R¹⁵ is selected from the group consisting of hydrogen, alkyl,    haloalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl,    and optionally substituted heteroarylalkyl.

Another embodiment of a compound of formula (Ib) is a compound offormula (Ib)

wherein:

-   n is 0;-   m is 0 to 1;-   R¹, R², R⁴ and R⁵ are each independently hydrogen, alkyl,    cycloalkylalkyl, or —R¹⁴—OR¹⁵;-   R^(3a), R^(3b), R^(3c), R^(3d) and R^(3e) are each independently    selected from the group consisting of hydrogen, alkyl, halo,    haloalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl, or    optionally substituted heteroarylalkyl;-   R⁶, R⁷ and R⁸ are each independently alkyl, haloalkyl, or —R¹³—OR¹⁵;-   R¹⁶ is alkyl, halo or haloalkyl;-   R¹³ is selected from the group consisting of a direct bond or an    optionally substituted straight or branched alkylene chain;-   R¹⁴ is an optionally substituted straight or branched alkylene    chain; and-   R¹⁵ is selected from the group consisting of hydrogen, alkyl,    haloalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl,    and optionally substituted heteroarylalkyl.

Another embodiment of a compound of formula (Ib) is a compound offormula (Ib)

wherein:

-   n is 0;-   m is 0 to 1;-   R¹, R², R⁴ and R⁵ are each independently hydrogen, alkyl,    cycloalkylalkyl, or —R¹⁴—OR¹⁵;-   R^(3a), R^(3b), and R^(3e) are each hydrogen;-   R^(3c) and R^(3d) are each independently selected from the group    consisting of hydrogen, alkyl, halo, haloalkyl, optionally    substituted heterocyclyl, optionally substituted heterocyclylalkyl,    optionally substituted heteroaryl, or optionally substituted    heteroarylalkyl;-   R⁶, R⁷ and R⁸ are each independently alkyl, haloalkyl, or —R¹³—OR¹⁵;-   R¹⁰ is alkyl, halo or haloalkyl;-   R¹³ is selected from the group consisting of a direct bond or an    optionally substituted straight or branched alkylene chain;-   R¹⁴ is an optionally substituted straight or branched alkylene    chain; and-   R¹⁵ is selected from the group consisting of hydrogen, alkyl,    haloalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl,    and optionally substituted heteroarylalkyl.

Another embodiment of a compound of formula (Ib) is a compound offormula (Ib) which is(1S,2S,3R,5S)-2-(5-chloro-2-(4-morpholinophenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide.

Another embodiment of a compound of formula (Ib) is a compound offormula (Ib)

wherein:

-   n is 0;-   m is 0 to 1;-   R¹, R², R⁴ and R⁵ are each independently hydrogen, alkyl,    cycloalkylalkyl, or —R¹⁴—OR¹⁵; R^(3a), R^(3b), R^(3c), R^(3d) and    R^(3e) are each independently selected from the group consisting of    hydrogen, alkyl, halo, haloalkyl, —R¹⁷—OR¹⁶, —R¹⁷—N(R¹⁶)₂,    —R¹⁷—C(O)R¹⁶, —R¹⁷—C(O)OR¹⁶, —R¹⁷—C(O)N(R¹⁶)₂,    —R¹⁷—O—R¹⁸—C(O)N(R¹⁶)₂, —R¹⁷—O—R¹⁸—N(R¹⁶)₂, and —R¹⁷—S(O)_(t)N(R¹⁶)₂    (where t is 1 or 2), where each R¹⁶ is independently hydrogen,    alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted heterocyclyl, optionally substituted heterocyclylalkyl,    optionally substituted heteroaryl or optionally substituted    heteroarylalkyl, each R¹⁷ is independently a direct bond or a    straight or branched alkylene or alkenylene chain, and R¹⁸ is a    straight or branched alkylene or alkenylene chain;-   R⁶, R⁷ and R⁸ are each independently alkyl, haloalkyl, or —R¹³—OR¹⁵;-   R¹⁰ is alkyl, halo or haloalkyl;-   R¹³ is selected from the group consisting of a direct bond or an    optionally substituted straight or branched alkylene chain;-   R¹⁴ is an optionally substituted straight or branched alkylene    chain; and-   R¹⁵ is selected from the group consisting of hydrogen, alkyl,    haloalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl,    and optionally substituted heteroarylalkyl.

Another embodiment of a compound of formula (Ib) is a compound offormula (Ib)

wherein:

-   n is 0;-   m is 0 to 1;-   R¹, R², R⁴ and R⁵ are each independently hydrogen, alkyl,    cycloalkylalkyl, or —R¹⁴—OR¹⁵;-   R^(3e), R^(3b) and R^(3e) are each hydrogen;-   R^(3c) and R^(3d) are each independently selected from the group    consisting of hydrogen, alkyl, halo, haloalkyl, —R¹⁷—OR¹⁶,    —R¹⁷—N(R¹⁶)₂, —R¹⁷—C(O)R¹⁶, —R¹⁷—C(O)OR¹⁶, —R¹⁷—C(O)N(R¹⁶)₂,    —R¹⁷—O—R¹⁸—C(O)N(R¹⁶)₂, —R¹⁷—O—R¹⁸—N(R¹⁶)₂, and —R¹⁷—S(O)₁N(R¹⁶)₂    (where t is 1 or 2), where each R¹⁶ is independently hydrogen,    alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted heterocyclyl, optionally substituted heterocyclylalkyl,    optionally substituted heteroaryl or optionally substituted    heteroarylalkyl, each R¹⁷ is independently a direct bond or a    straight or branched alkylene or alkenylene chain, and R¹⁸ is a    straight or branched alkylene or alkenylene chain;-   R⁶, R⁷ and R⁸ are each independently alkyl, haloalkyl, or —R¹³—OR¹⁵;-   R¹⁰ is alkyl, halo or haloalkyl;-   R¹³ is selected from the group consisting of a direct bond or an    optionally substituted straight or branched alkylene chain;-   R¹⁴ is an optionally substituted straight or branched alkylene    chain; and-   R¹⁵ is selected from the group consisting of hydrogen, alkyl,    haloalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl,    and optionally substituted heteroarylalkyl.

Another embodiment of a compound of formula (Ib) is a compound offormula (Ib) selected from the group consisting of:

-   (1S,2S,3R,5S)-2-(5-chloro-2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;    and-   (1S,2S,3R,5S)-2-(5-chloro-2-(3-fluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide.

Of the various aspects of the invention set forth above in the Summaryof the Invention, certain embodiments of the compounds of formula (Ic),as described above in the Summary of the Invention, are preferred.

One embodiment of a compound of formula (Ic) is a compound of formula(Ic)

wherein:

-   n is 0 to 4;-   m is 0 to 1;

q is 0 to 4;

Y is ═C(R^(3b))— or ═N—;

-   R¹, R², R⁴ and R⁵ are each independently hydrogen, alkyl,    cycloalkylalkyl, —R¹⁴—OR¹⁵, —C(O)R¹⁵ or —C(O)N(R¹¹)R¹²;-   R^(3b) and R^(3e) are each independently selected from the group    consisting of hydrogen, alkyl, halo, haloalkyl, cyano, nitro,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl,    optionally substituted heteroarylalkyl, —R¹⁷—OR¹⁶, —R¹⁷—N(R¹⁶)₂,    —R¹⁷—C(O)R¹⁶, —R¹⁷—C(O)OR¹⁶, —R¹⁷—C(O)N(R¹⁶)₂, —R¹⁷—N(R¹⁶)C(O)OR¹⁶,    —R¹⁷—N(R¹⁶)C(O)R¹⁶, —R¹⁷—N(R¹⁶)S(O)_(t)R¹⁶ (where t is 1 or 2),    —R¹⁷—S(O)_(t)OR¹⁶ (where t is 1 or 2), —R¹⁷—S(O)_(p)R¹⁶ (where p is    0, 1 or 2), and —R¹⁷—S(O)_(t)N(R¹⁶)₂ (where t is 1 or 2), where each    R¹⁶ is independently hydrogen, alkyl, haloalkyl, cycloalkyl,    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl or optionally    substituted heteroarylalkyl, each R¹⁷ is independently a direct bond    or a straight or branched alkylene or alkenylene chain, and R¹⁸ is a    straight or branched alkylene or alkenylene chain;-   R^(3f) is independently selected from the group consisting of    hydrogen, alkyl, haloalkyl, optionally substituted aralkyl,    optionally substituted cycloalkylalkyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroarylalkyl, and    —R¹⁴—N(R¹⁵)₂, where R¹⁴ is an optionally substituted straight or    branched alkylene chain and R¹⁵ is selected from the group    consisting of hydrogen, alkyl, haloalkyl, optionally substituted    aryl, optionally substituted aralkyl;-   each R^(3g) is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl,    haloalkynyl, cyano, nitro, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted cycloalkyl, optionally    substituted cycloalkylalkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, —R¹⁷—OR¹⁶,    —R¹⁷—N(R¹⁶)₂, —R¹⁷—C(O)R¹⁶, —R¹⁷—C(O)OR¹⁶, —R¹⁷—C(O)N(R¹⁶)₂,    —R¹⁷—N(R¹⁶)C(O)OR¹⁶, —R¹⁷—N(R¹⁶)C(O)R¹⁶, —R¹⁷—N(R¹⁶)S(O)_(t)R¹⁶    (where t is 1 or 2), —R¹⁷—S(O)_(t)OR¹⁶ (where t is 1 or 2),    —R¹⁷—S(O)_(p)R¹⁶ (where p is 0, 1 or 2), and —R¹⁷—S(O)_(t)N(R¹⁶)₂    (where t is 1 or 2), where each R¹⁶ is independently hydrogen,    alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted heterocyclyl, optionally substituted heterocyclylalkyl,    optionally substituted heteroaryl or optionally substituted    heteroarylalkyl, each R¹⁷ is independently a direct bond or a    straight or branched alkylene or alkenylene chain, and R¹⁸ is a    straight or branched alkylene or alkenylene chain; or two R^(3g)'s,    together with the common carbon to which they are both attached,    form an oxo, or two R^(3g)'s on adjacent carbons form a double bond;-   R⁶, R⁷ and R⁸ are each independently alkyl, haloalkyl, or —R¹³—OR¹⁵;-   each R⁹ and R¹⁰ is independently alkyl, halo, haloalkyl, aryl or    aralkyl;-   R¹¹ and R¹² are each independently selected from the group    consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, —R¹⁴—OR¹⁵, —R¹⁴—CN, —R¹⁴—NO₂,    —R¹⁴—N(R¹⁵)₂, —R¹⁴—C(O)OR¹⁵ and —R¹⁴—C(O)N(R¹⁵)₂;-   R¹³ is independently selected from the group consisting of a direct    bond or an optionally substituted straight or branched alkylene    chain;-   each R¹⁴ is an optionally substituted straight or branched alkylene    chain; and-   each R¹⁵ is independently selected from the group consisting of    hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted cycloalkyl, optionally    substituted cycloalkylalkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, optionally substituted    heteroaryl, and optionally substituted heteroarylalkyl.

Another embodiment of a compound of formula (Ic) is a compound offormula (Ic)

wherein:

-   n is 0;-   m is 0 to 1;-   q is 0 to 4;-   Y is ═C(R^(3b))— or ═N—;-   R¹, R², R⁴ and R⁵ are each independently hydrogen, alkyl,    cycloalkylalkyl, —R¹⁴—OR¹⁵, —C(O)R¹⁵ or —C(O)N(R¹¹)R¹²;-   R^(3b) and R^(3e) are each hydrogen;-   R^(3f) is hydrogen, optionally substituted heterocyclylalkyl, or    —R¹⁴—N(R¹⁵)₂, where R¹⁴ is an optionally substituted straight or    branched alkylene chain and R¹⁵ is selected from the group    consisting of hydrogen, alkyl, haloalkyl, optionally substituted    aryl, optionally substituted aralkyl;-   each R^(3g) is independently selected from the group consisting of    hydrogen, alkyl, halo, and haloalkyl; or two R^(3g)'s, together with    the common carbon to which they are both attached, form an oxo, or    two R^(3g)'s on adjacent carbons form a double bond;-   R⁶, R⁷ and R⁸ are each independently alkyl, haloalkyl, or —R¹³—OR¹⁵;-   R¹⁰ is alkyl, halo, haloalkyl, aryl or aralkyl;-   R¹¹ and R¹² are each independently selected from the group    consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, —R¹⁴—OR¹⁵, —R¹⁴—CN, —R¹⁴—NO₂,    —R¹⁴—N(R¹⁵)₂, —R¹⁴—C(O)OR¹⁵ and —R¹⁴—C(O)N(R¹⁵)₂;-   R¹³ is independently selected from the group consisting of a direct    bond or an optionally substituted straight or branched alkylene    chain;-   each R¹⁴ is an optionally substituted straight or branched alkylene    chain; and-   each R¹⁵ is independently selected from the group consisting of    hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted cycloalkyl, optionally    substituted cycloalkylalkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, optionally substituted    heteroaryl, and optionally substituted heteroarylalkyl.

Another embodiment of a compound of formula (Ic) is a compound offormula (Ic)

wherein:

-   n is 0;-   m is 0 to 1;-   q is 0 to 4;-   Y is ═C(R^(3b))— or ═N—;-   R¹, R², R⁴ and R⁵ are each independently hydrogen, alkyl,    cycloalkylalkyl, or —R¹⁴—OR¹⁵;-   R^(3b) and R^(3e) are each hydrogen;-   R^(3f) is hydrogen or —R¹⁴—N(R¹⁵)₂, where R¹⁴ is an optionally    substituted straight or branched alkylene chain and R¹⁵ is selected    from the group consisting of hydrogen, alkyl, haloalkyl, optionally    substituted aryl, optionally substituted aralkyl;-   each R^(3g) is independently selected from the group consisting of    hydrogen, alkyl, halo, and haloalkyl; or two R^(3g)'s, together with    the common carbon to which they are both attached, form an oxo, or    two R^(3g)'s on adjacent carbons form a double bond;-   R⁶, R⁷ and R⁸ are each independently alkyl, haloalkyl, or —R¹³—OR¹⁵;-   R¹⁰ is alkyl, halo, haloalkyl, aryl or aralkyl;-   R¹³ is independently selected from the group consisting of a direct    bond or an optionally substituted straight or branched alkylene    chain;-   each R¹⁴ is an optionally substituted straight or branched alkylene    chain; and-   each R¹⁵ is independently selected from the group consisting of    hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted cycloalkyl, optionally    substituted cycloalkylalkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, optionally substituted    heteroaryl, and optionally substituted heteroarylalkyl.

Another embodiment of a compound of formula (Ic) is a compound offormula (Ic) selected from the group consisting of:

-   (1R,2R,3S,5R)-2-(5-chloro-2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-ylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-chloro-2-((3,4-dihydro-4-(2-(diethylamino)ethyl)-2H-benzo[b][1,4]oxazin-7-yl)amino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-fluoro-2-((3,4-dihydro-4-(2-(diethylamino)ethyl)-2H-benzo[b][1,4]oxazin-7-yl)amino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-chloro-2-((3,4-dihydro-4-(2-(dimethylamino)ethyl)-2H-benzo[b][1,4]oxazin-7-yl)amino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-fluoro-2-((3,4-dihydro-4-(2-(dimethylamino)ethyl)-2H-benzo[b][1,4]oxazin-7-yl)amino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-methyl-2-((3,4-dihydro-4-(2-(dimethylamino)ethyl)-2H-benzo[b][1,4]oxazin-7-yl)amino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-chloro-2-((3,4-dihydro-4-(2-(dimethylamino)ethyl)-2H-benzo[b][1,4]oxazin-6-yl)amino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-fluoro-2-((3,4-dihydro-4-(2-(dimethylamino)ethyl)-2H-benzo[b][1,4]oxazin-6-yl)amino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-trifluoromethyl-2-((3,4-dihydro-4-(2-(diethylamino)ethyl)-2H-benzo[b][1,4]oxazin-7-yl)amino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-chloro-2-((3,4-dihydro-4-(2-(dimethylamino)ethyl)-2H-benzo[b][1,4]oxazin-7-yl)amino)pyrimidin-4-ylamino)-N-(2-hydroxyethyl)-2,6,6-trimethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-chloro-2-((3,4-dihydro-4-(2-(dimethylamino)ethyl)-2H-benzo[b][1,4]oxazin-7-yl)amino)pyrimidin-4-ylamino)-N-(1-methylethyl)-2,6,6-trimethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-chloro-2-(2,2-difluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-ylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide.

Another embodiment of a compound of formula (Ic) is a compound offormula (Ic)

wherein:

-   n is 0;-   m is 0 to 1;-   q is 0 to 4;-   Y is ═C(R^(3b))— or ═N—;-   R¹, R², R⁴ and R⁵ are each independently hydrogen, alkyl,    cycloalkylalkyl, or —R¹⁴—OR¹⁵;-   R^(3b) and R^(3e) are each hydrogen;-   R^(3f) is optionally substituted heterocyclylalkyl;-   each R^(3g) is independently selected from the group consisting of    hydrogen, alkyl, halo, and haloalkyl; or two R^(3g)'s, together with    the common carbon to which they are both attached, form an oxo, or    two R^(3g)'s on adjacent carbons form a double bond;-   R⁶, R⁷ and R⁸ are each independently alkyl, haloalkyl, or —R¹³—OR¹⁵;-   R¹⁰ is alkyl, halo, haloalkyl, aryl or aralkyl;-   R¹³ is independently selected from the group consisting of a direct    bond or an optionally substituted straight or branched alkylene    chain;-   each R¹⁴ is an optionally substituted straight or branched alkylene    chain; and-   each R¹⁵ is independently selected from the group consisting of    hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted cycloalkyl, optionally    substituted cycloalkylalkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, optionally substituted    heteroaryl, and optionally substituted heteroarylalkyl.

Another embodiment of a compound of formula (Ic) is a compound offormula (Ic) selected from the group consisting of:

-   (1R,2R,3S,5R)-2-(5-chloro-2-((3,4-dihydro-4-(2-(piperidin-1-yl)ethyl)-2H-benzo[b][1,4]oxazin-7-yl)amino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-fluoro-2-((3,4-dihydro-4-(2-(piperidin-1-yl)ethyl)-2H-benzo[b][1,4]oxazin-7-yl)amino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;-   (1R,2R,3S,5R)-2-(5-chloro-2-((3,4-dihydro-4-(2-(morpholin-4-yl)ethyl)-2H-benzo[b][1,4]oxazin-7-yl)amino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;    and-   (1R,2R,3S,5R)-2-(5-fluoro-2-((3,4-dihydro-4-(2-(morpholin-4-yl)ethyl)-2H-benzo[b][1,4]oxazin-7-yl)amino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide.

Of the various aspects of the invention set forth above in the Summaryof the Invention, certain embodiments of the compounds of formula (Id),as described above in the Summary of the Invention, are preferred.

One embodiment of a compound of formula (Id) is a compound of formula(Id)

wherein:

-   n is 0 to 4;-   m is 0 to 1;-   q is 0 to 4;-   R¹, R², R⁴ and R⁵ are each independently hydrogen, alkyl,    cycloalkylalkyl, —R¹⁴—OR¹⁵, —C(O)R¹⁵ or —C(O)N(R¹¹)R¹²;-   R^(3b) and R^(3e) are each independently selected from the group    consisting of hydrogen, alkyl, halo, haloalkyl, cyano, nitro,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl,    optionally substituted heteroarylalkyl, —R¹⁷—OR¹⁶, —R¹⁷—N(R¹⁶)₂,    —R¹⁷—C(O)R¹⁶, —R¹⁷—C(O)OR¹⁶, —R¹⁷—C(O)N(R¹⁶)₂, —R¹⁷—N(R¹⁶)C(O)OR¹⁶,    —R¹⁷—N(R¹⁶)C(O)R¹⁶, —R¹⁷—N(R¹⁶)S(O)_(t)R¹⁶ (where t is 1 or 2),    —R¹⁷—S(O)_(t)OR¹⁶ (where t is 1 or 2), —R¹⁷—S(O)_(p)R¹⁶ (where p is    0, 1 or 2), and —R¹⁷—S(O)_(t)N(R¹⁶)₂ (where t is 1 or 2), where each    R¹⁶ is independently hydrogen, alkyl, haloalkyl, cycloalkyl,    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl or optionally    substituted heteroarylalkyl, each R¹⁷ is independently a direct bond    or a straight or branched alkylene or alkenylene chain, and R¹⁸ is a    straight or branched alkylene or alkenylene chain;-   R^(3f) is independently selected from the group consisting of    hydrogen, alkyl, haloalkyl, optionally substituted aralkyl,    optionally substituted cycloalkylalkyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroarylalkyl, and    —R¹⁴—N(R¹⁵)₂, where R¹⁴ is an optionally substituted straight or    branched alkylene chain and R¹⁵ is selected from the group    consisting of hydrogen, alkyl, haloalkyl, optionally substituted    aryl, optionally substituted aralkyl; each R^(3g) is independently    selected from the group consisting of hydrogen, alkyl, alkenyl,    alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, cyano, nitro,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl,    optionally substituted heteroarylalkyl, —R¹⁷—OR¹⁶, —R¹⁷—N(R¹⁶)₂,    —R¹⁷—C(O)R¹⁶, —R¹⁷—C(O)OR¹⁶, —R¹⁷—C(O)N(R¹⁶)₂, —R¹⁷—N(R¹⁶)C(O)OR¹⁶,    —R¹⁷—N(R¹⁶)C(O)R¹⁶, —R¹⁷—N(R¹⁶)S(O)_(t)R¹⁶ (where t is 1 or 2),    —R¹⁷—S(O)_(t)OR¹⁶ (where t is 1 or 2), —R¹⁷—S(O)_(p)R¹⁶ (where p is    0, 1 or 2), and —R¹⁷—S(O)_(t)N(R¹⁶)₂ (where t is 1 or 2), where each    R¹⁶ is independently hydrogen, alkyl, haloalkyl, cycloalkyl,    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl or optionally    substituted heteroarylalkyl, each R¹⁷ is independently a direct bond    or a straight or branched alkylene or alkenylene chain, and R¹⁵ is a    straight or branched alkylene or alkenylene chain; or two R^(3g)'s,    together with the common carbon to which they are both attached,    form an oxo, or two R^(3g)'s on adjacent carbons form a double bond;-   R⁶, R⁷ and R⁸ are each independently alkyl, haloalkyl, or —R¹³—OR¹⁵;-   each R⁹ and R¹⁰ is independently alkyl, halo, haloalkyl, aryl or    aralkyl;-   R¹¹ and R¹² are each independently selected from the group    consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, —R¹⁴—OR¹⁵, —R¹⁴—CN, —R¹⁴—NO₂,    —R¹⁴—N(R¹⁵)₂, —R¹⁴—C(O)OR¹⁵ and —R¹⁴—C(O)N(R¹⁵)₂;-   R¹³ is independently selected from the group consisting of a direct    bond or an optionally substituted straight or branched alkylene    chain;-   each R¹⁴ is an optionally substituted straight or branched alkylene    chain; and-   each R¹⁵ is independently selected from the group consisting of    hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted cycloalkyl, optionally    substituted cycloalkylalkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, optionally substituted    heteroaryl, and optionally substituted heteroarylalkyl.

Another embodiment of a compound of formula (Id) is a compound offormula (Id)

wherein:

-   n is 0;-   m is 0 to 1;-   q is 0 to 4;-   R¹, R², R⁴ and R⁵ are each independently hydrogen, alkyl,    cycloalkylalkyl, —R¹⁴—OR¹⁵, —C(O)R¹⁵ or —C(O)N(R¹¹)R¹²;-   R^(3b) and R^(3e) are each hydrogen;-   R^(3f) is hydrogen, optionally substituted heterocyclylalkyl, or    —R¹⁴—N(R¹⁵)₂, where R¹⁴ is an optionally substituted straight or    branched alkylene chain and R¹⁵ is selected from the group    consisting of hydrogen, alkyl, haloalkyl, optionally substituted    aryl, optionally substituted aralkyl;-   each R^(3g) is independently selected from the group consisting of    hydrogen, alkyl, halo, and haloalkyl; or two R^(3g)'s, together with    the common carbon to which they are both attached, form an oxo, or    two R^(3g)'s on adjacent carbons form a double bond;-   R⁶, R⁷ and R⁸ are each independently alkyl, haloalkyl, or —R¹³—OR¹⁵;-   R¹⁰ is alkyl, halo, haloalkyl, aryl or aralkyl;-   R¹¹ and R¹² are each independently selected from the group    consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, —R¹⁴—OR¹⁵, —R¹⁴—CN, —R¹⁴—NO₂,    —R¹⁴—N(R¹⁵)₂, —R¹⁴—C(O)OR¹⁵ and —R¹⁴—C(O)N(R¹⁵)₂;-   R¹³ is independently selected from the group consisting of a direct    bond or an optionally substituted straight or branched alkylene    chain;-   each R¹⁴ is an optionally substituted straight or branched alkylene    chain; and-   each R¹⁵ is independently selected from the group consisting of    hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted cycloalkyl, optionally    substituted cycloalkylalkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, optionally substituted    heteroaryl, and optionally substituted heteroarylalkyl.

Another embodiment of a compound of formula (Id) is a compound offormula (Id)

wherein:

-   n is 0;-   m is 0 to 1;-   q is 0 to 4;-   R¹, R², R⁴ and R⁵ are each independently hydrogen, alkyl,    cycloalkylalkyl, or —R¹⁴—OR¹⁵;-   R^(3b) and R^(3e) are each hydrogen;-   R^(3f) is hydrogen or —R¹⁴—N(R¹⁵)₂, where R¹⁴ is an optionally    substituted straight or branched alkylene chain and R¹⁵ is selected    from the group consisting of hydrogen, alkyl, haloalkyl, optionally    substituted aryl, optionally substituted aralkyl;-   each R^(3g) is independently selected from the group consisting of    hydrogen, alkyl, halo, and haloalkyl; or two R^(3g)'s, together with    the common carbon to which they are both attached, form an oxo, or    two R^(3g)'s on adjacent carbons form a double bond;-   R⁶, R⁷ and R⁸ are each independently alkyl, haloalkyl, or —R¹³—OR¹⁵;-   R¹⁰ is alkyl, halo, haloalkyl, aryl or aralkyl;-   R¹³ is independently selected from the group consisting of a direct    bond or an optionally substituted straight or branched alkylene    chain;-   each R¹⁴ is an optionally substituted straight or branched alkylene    chain; and-   each R¹⁵ is independently selected from the group consisting of    hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted cycloalkyl, optionally    substituted cycloalkylalkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, optionally substituted    heteroaryl, and optionally substituted heteroarylalkyl.

Another embodiment of a compound of formula (Id) is a compound offormula (Id) selected from the group consisting of:

-   (1R,2R,3S,5R)-2-(2-(1H-indol-5-ylamino)-5-chloropyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;    and-   (1R,2R,3S,5R)-2-(5-chloro-2-(1-(2-(dimethylamino)ethyl)indolin-5-ylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide.

Of the various aspects of the pharmaceutical compositions of theinvention comprising a pharmaceutically acceptable excipient and atherapeutically effective amount of a compound of formula (Ia), acompound of formula (Ib), a compound of formula (Ic) or a compound offormula (Id), as set forth above in the Summary of the Invention,certain embodiments are preferred.

One embodiment of these pharmaceutical compositions is wherein thecompound of formula (Ia) therein is selected from any one embodiment ofthe compound of formula (Ia), as set forth above, or from anycombination of embodiments of the compound of formula (Ia), as set forthabove, or the compound of formula (Ib) therein is selected from any oneembodiment of the compound of formula (Ib), as set forth above, or fromany combination of embodiments of the compound of formula (Ib), as setforth above, or the compound of formula (Ic) therein is selected fromany one embodiment of the compound of formula (Ic), as set forth above,or from any combination of embodiments of the compound of formula (Ic),as set forth above, or the compound of formula (Id) therein is selectedfrom any one embodiment of the compound of formula (Id), as set forthabove, or from any combination of embodiments of the compound of formula(Id), as set forth above.

Of the various aspects of methods of treating a disease or conditionassociated with Axl activity in a mammal, wherein the method comprisesadministering to a mammal in need thereof a therapeutically effectiveamount of a compound of formula (Ia), a compound of formula (Ib), acompound of formula (Ic) or a compound of formula (Ib), certainembodiments are preferred.

One embodiment of these methods is the method wherein the disease orcondition is selected from the group consisting of rheumatoid arthritis,vascular disease, vascular injury, psoriasis, visual impairment due tomacular degeneration, diabetic retinopathy, retinopathy of prematurity,kidney disease, osteoporosis, osteoarthritis and cataracts.

One embodiment of these methods is the method wherein a manifestation ofthe disease or condition is solid tumor formation in said mammal.

One embodiment of these methods is the method wherein the disease orcondition is selected from the group consisting of breast carcinoma,renal carcinoma, endometrial carcinoma, ovarian carcinoma, thyroidcarcinoma, non-small cell lung carcinoma, and uveal melanoma.

One embodiment of these methods is the method wherein a manifestation ofthe disease or condition is liquid tumor formation in said mammal.

One embodiment of these methods is the method wherein the disease orcondition is myeloid leukemia or lymphoma.

One embodiment of these methods is the method wherein the disease orcondition is endometriosis.

One embodiment of these methods is the method wherein the compounds offormula (Ia) utilized therein is selected from any one embodiment of thecompound of formula (Ia), as set forth above, or from any combination ofembodiments of the compound of formula (Ia), as set forth above, or thecompound of formula (Ib) therein is selected from any one embodiment ofthe compound of formula (Ib), as set forth above, or from anycombination of embodiments of the compound of formula (Ib), as set forthabove, or the compound of formula (Ic) therein is selected from any oneembodiment of the compound of formula (Ic), as set forth above, or fromany combination of embodiments of the compound of formula (Ic), as setforth above, or the compound of formula (Id) therein is selected fromany one embodiment of the compound of formula (Id), as set forth above,or from any combination of embodiments of the compound of formula (Id),as set forth above.

Another embodiment of the invention are those methods of treating adisease or condition associated with Axl activity by administering tothe mammal a therapeutically effective amount of a pharmaceuticalcomposition of the invention, as set forth above in the Summary of theInvention, wherein the disease or condition is selected from the groupconsisting of rheumatoid arthritis, vascular disease/injury (includingbut not limited to restenosis, atherosclerosis and thrombosis),psoriasis, visual impairment due to macular degeneration, diabeticretinopathy or retinopathy of prematurity, kidney disease (including butnot limited to glomerulonephritis, diabetic nephropathy and renaltransplant rejection), osteoporosis, osteoarthritis and cataracts.

Another embodiment of the invention are those methods of treating adisease or condition associated with Axl activity by administering tothe mammal a therapeutically effective amount of a pharmaceuticalcomposition of the invention, as set forth above in the Summary of theInvention, wherein the disease or condition is selected from the groupconsisting of breast carcinoma, renal carcinoma, endometrial carcinoma,ovarian carcinoma, thyroid carcinoma, non-small cell lung carcinoma,melanoma, prostate carcinoma, sarcoma, gastric cancer, uveal melanoma,myeloid leukemia and lymphoma.

Another embodiment of the invention are those methods of treating adisease or condition associated with Axl activity by administering tothe mammal of therapeutically effective amount of a pharmaceuticalcomposition of the invention, as set forth above in the Summary of theInvention, wherein the disease or condition is endometriosis.

It is understood that any embodiment of the compounds of formula (Ia),compounds of formula (Ib), compounds of formula (Ic) and compounds offormula (Id), as set forth above, and any specific substituent set forthherein for a R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ group in thecompounds of formula (Ia), the compounds of formula (Ib), the compoundsof formula (Ic) or the compounds of formula (Id), as set forth above,may be independently combined with other embodiments and/or substituentsof compounds of formula (Ia), compounds of formula (Ib), compounds offormula (Ic) and compounds of formula (Id) to form embodiments of theinventions not specifically set forth above. In addition, in the eventthat a list of substitutents is listed for any particular R group in aparticular embodiment and/or claim, it is understood that eachindividual substituent may be deleted from the particular embodimentand/or claim and that the remaining list of substituents will beconsidered to be enabled by this disclosure.

Specific embodiments of the invention are described in more detail belowin the following sections.

Utility and Testing of the Compounds of the Invention

The oncogenic RTK, Axl, was recently identified, using aretroviral-based functional genetic screening protocol, as a regulatorof haptotactic migration, which is a key event in angiogenesis. Axlinhibition by RNAi-mediated silencing blocked endothelial cellmigration, proliferation and in vitro tube formation. Theseobservations, which were disclosed at the American Association CancerResearch General Meeting, Apr. 16-20, 2005, Anaheim, Calif., and The 7thAnnual Symposium on Anti-Angiogenic Agents, Feb. 10-13, 2005, San Diego,Calif.; (Requirement for The Receptor Tyrosine Kinase Axl inAngiogenesis and Tumor Growth, Holland, S. J. Powell, M. J., Franci, C.,Chan, E., Friera, A. M., Atchison, R., Xu, W., McLaughlin, J., Swift, S.E., Pali, E., Yam, G., Wong, S., Xu, X., Hu, Y., Lasaga, J., Shen, M.,Yu, S., Daniel, R., Hitoshi, Y., Bogenberger, J., Nor, J. E., Payan, D.G and Lorens, J. B), were substantiated by an in vivo study whichdemonstrated that stable, shRNAi-mediated Axl knockdown impairedformation of functional human blood vessels in a mouse model of humanangiogenesis. These observations were published in a peer reviewedjournal (Holland S J, Powell M J, Franci C, Chan E W, Friera A M,Atchison R E, McLaughlin J, Swift S E, Pali E S, Yam G, Wong S, LasagaJ, Shen M R, Yu S, Xu W, Hitoshi Y, Bogenberger J, Nor J E, Payan D G,Lorens J B. “Multiple roles for the receptor tyrosine kinase axl intumor formation.” Cancer Res. (2005) Vol 65 pp 9294-303. Theseobservations are also disclosed in U.S. Published Patent Application2005/0118604 and European Patent Application 1 563 094, the disclosuresof which are incorporated in full by reference. Axl signaling,therefore, impacts multiple functions required for neovascularization invitro, and regulates angiogenesis in vivo. Regulation of thesepro-angiogenic processes required the catalytic activity of Axl. Thus,Axl-mediated angiogenic stimulation would be amenable to modulation by asmall molecule inhibitor of Axl catalytic activity.

Accordingly, the compounds of the invention are small moleculeinhibitors of Axl catalytic activity, and are therefore useful intreating diseases and conditions which are associated with Axl catalyticactivity including those diseases and conditions which are characterizedby angiogenesis and/or cell proliferation. In particular, the compoundsof the invention and pharmaceutical compositions of the invention areuseful in treating diseases and conditions which are alleviated by themodulation of Axl activity. For purposes of this invention, diseases andconditions which are alleviated by the “modulation of Axl activity”includes diseases and conditions which are alleviated by a decrease inAxl activity and diseases and conditions which are alleviated by anincrease in Axl activity. Preferably such diseases and conditions arealleviated by a decrease in Axl activity. Diseases and conditions whichare alleviated by the modulation of Axl activity include, but are notlimited to, solid tumors, including, but not limited to, breast, renal,endometrial, ovarian, thyroid, non-small cell lung carcinoma, melanoma,prostate carcinoma, sarcoma, gastric cancer and uveal melanoma; liquidtumors, including but not limited to, leukemias (particularly myeloidleukemias) and lymphomas; endometriosis, vascular disease/injury(including but not limited to restenosis, atherosclerosis andthrombosis), psoriasis; visual impairment due to macular degeneration;diabetic retinopathy and retinopathy of prematurity; kidney disease(including but not limited to glomerulonephritis, diabetic nephropathyand renal transplant rejection), rheumatoid arthritis; osteoarthritis,osteoporosis and cataracts. Additional solid tumors which may beassociated with Axl activity include solid tumors of the tongue, mouth,pharynx, esophagus, stomach, small intestine, colon, rectum, anus,liver, gallbladder, pancreas, larynx, lung and bronchus, bones andjoints including synovial sarcoma and osteosarcoma, melanomas includingbasal cell carcinoma, squamous carcinoma, breast, cervix, endometrium,ovary, vulva, vagina, prostate, testis, penis, urinary bladder, kidneyand renal, pelvis, ureter, eye, brain including glioma, glioblastoma,astrocytoma, neuroblastoma, medulloblastoma, and thyroid.

The following animal models provide guidance to one of ordinary skill inthe art in testing the compounds of the invention for their use intreating the disease or condition indicated.

The compounds of the invention may be tested for their use in treatingleukemias and lymphomas by testing the compounds in the xenograft inSCID mouse model using human Axl-expressing cancer cell lines including,but not limited to, HeLa, MDA-MB-231, SK-OV-3, OVCAR-8, DU145, H1299,ACHN, A498 and Caki-1.

The compounds of the invention may be tested for their use in treatingleukemias in the xenograft in SCID or nu/nu mouse model using humanAxl-expressing AML and CML leukemia cell lines.

The compounds of the invention may be tested for their use in treatingendometriosis by using the syngenic mouse model of endometriosis (seeSomigliana, E. et al., “Endometrial ability to implant in ectopic sitescan be prevented by interleukin-12 in a murine model of endometriosis”,Hum. Reprod. (1999), Vol. 14, NO. 12, pp. 2944-50). The compounds mayalso be tested for their use in treating endometriosis by using the ratmodel of endometriosis (see Lebovic, D. I. et al., “Peroxisomeproliferator-activated receptor-gamma induces regression of endometrialexplants in a rat model of endometriosis”, Fertil. Steril. (2004), 82Suppl 3, pp. 1008-13).

The compounds of the invention may be tested for their use in treatingrestenosis by using the balloon-injured rate carotid artery model (seeKim, D. W. et al., “Novel oral formulation of paclitaxel inhibitsneointimal hyperplasia in a rat carotid artery injury model”,Circulation (2004), Vol. 109, No. 12, pp. 1558-63, Epub 2004 Mar. 8).

The compounds of the invention may also be tested for their use intreating restenosis by using the percutaneous transluminal coronaryangioplasty in apoE deficient mouse model (see von der Thusen, J. H. etal., “Adenoviral transfer of endothelial nitric oxide synthaseattenuates lesion formation in a novel murine model of postangioplastyrestenosis”, Arterioscler. Thromb. Vasc. Biol. (2004), Vol. 24, No. 2,pp. 357-62).

The compounds of the invention may be tested for their use in treatingatherosclerosis/thrombosis in the ApoE deficient mouse model (seeNakashima, Y. et al., “ApoE-deficient mice develop lesions of all phasesof atherosclerosis throughout the arterial tree”, Arterioscler. Thromb.(1994), Vol. 14, No. 1, pp. 133-40).

The compounds of the invention may also be tested for their use intreating thrombosis using the collagen-epinephrin-induced pulmonarythromboembolism model and the stasis induced venous thrombosis model(see Angelillo-Scherrer A. et al., “Role of Gas6 receptors in plateletsignaling during thrombus stabilization and implications forantithrombotic therapy”, J Clin Invest. (2005) Vol 115 pp 237-46).

The compounds of the invention may be tested for their use in treatingpsoriasis by using the SCID mouse model or the human skin model ofpsoriasis (see Nickoloff, B. J. et al., “Severe combinedimmunodeficiency mouse and human psoriatic skin chimeras. Validation ofa new animal model”, Am. J. Pathol. (1995), Vol. 146, No. 3, pp. 580-8).

The compounds of the invention may be tested for their use in treatingage-related macular degeneration or diabetic retinopathy by using therat corneal angiogenesis model (see Sarayba M A, Li L, Tungsiripat T,Liu N H, Sweet P M, Patel A J, Osann K E, Chittiboyina A, Benson S C,Pershadsingh H A, Chuck R S. Inhibition of corneal neovascularization bya peroxisome proliferator-activated receptor-gamma ligand. Exp Eye Res.2005 March; 80(3):435-42) or the laser-induced mouse choroidalneovasculation model (see Bora, P. S., et al., “Immunotherapy forchoroidal neovascularization in a laser-induced mouse model simulatingexudative (wet) macular degeneration”, Proc. Natl. Acad. Sci. U.S.A.(2003), Vol. 100, No. 5, pp. 2679-84, Epub 2003 Feb. 14).

The compounds of the invention may be tested for their use in treatingretinopathy of prematurity in the mouse retinopathy of prematurity model(see Smith, L. E. et al., “Oxygen-induced retinopathy in the mouse”,Invest. Ophthalmol. Vis. Sci. (1994), Vol. 35, No. 1, pp. 101-11).

The compounds of the invention may be tested for their use in treatingglomerulonephritis or diabetic nephropathy in the ratanti-Thy1.1-induced experimental mesengial proliferativeglomerulonephritis model (see Smith, L. E. et al. cited above).

The compounds of the invention may be tested for their use in treatingrenal tranplant rejection by using a rat model of chronic renaltransplant rejection (see Yin, J. L. et al., “Expression of growtharrest-specific gene 6 and its receptors in a rat model of chronic renaltransplant rejection”, Transplantation (2002), Vol. 73, No. 4, pp.657-60).

The compounds of the invention may be tested for their use in treatingrheumatoid arthritis by using the CAIA mouse model (see Phadke, K. etal., “Evaluation of the effects of various anti-arthritic drugs on typeII collagen-induced mouse arthritis model”, Immunopharmacology (1985),Vol. 10, No. 1, pp. 51-60).

The compounds of the invention may be tested for their use in treatingosteoarthritis by using the STR/ORT mouse model (see Brewster, M. etal., “Ro 32-3555, an orally active collagenase selective inhibitor,prevents structural damage in the STR/ORT mouse model ofosteoarthritis”, Arthritis. Rheum. (1998), Vol. 41, No. 9, pp. 1639-44).

The compounds of the invention may be tested for their use in treatingosteoporosis by using the ovariectomized rat model (see Wronski, T. J.et al., “Endocrine and pharmacological suppressors of bone turnoverprotect against osteopenia in ovariectomized rats”, Endocrinology(1989), Vol. 125, no. 2, pp 810-6) or the ovariectomized mouse model(see Alexander, J. M. et al., “Human parathyroid hormone 1-34 reversesbone loss in ovariectomized mice”, J Bone Miner Res. (2001), Vol. 16,no. 9, pp 1665-73; Fujioka, M. et al., “Equol, a metabolite of daidzein,inhibits bone loss in ovariectomized mice”, J Nutr. (2004), Vol. 134,no. 10, pp 2623-7).

The compounds of the invention may be tested for their use in treatingcataracts by using the H₂O₂-induced model (see Kadoya, K. et al., “Roleof calpain in hydrogen peroxide induced cataract”, Curr. Eye Res.(1993), Vol. 12, No. 4, pp. 341-6) or the Emory mouse model (see Sheets,N. L. et al., “Cataract- and lens-specific upregulation of ARK receptortyrosine kinase in Emory mouse cataract”, Invest. Ophthalmol. Vis.(2002), Vol. 43, No. 6, pp. 1870-5).

Pharmaceutical Compositions of the Invention and Administration

Administration of the compounds of the invention, or theirpharmaceutically acceptable salts, in pure form or in an appropriatepharmaceutical composition, can be carried out via any of the acceptedmodes of administration of agents for serving similar utilities. Thepharmaceutical compositions of the invention can be prepared bycombining a compound of the invention with an appropriatepharmaceutically acceptable carrier, diluent or excipient, and may beformulated into preparations in solid, semi-solid, liquid or gaseousforms, such as tablets, capsules, powders, granules, ointments,solutions, suppositories, injections, inhalants, gels, microspheres, andaerosols. Typical routes of administering such pharmaceuticalcompositions include, without limitation, oral, topical, transdermal,inhalation, parenteral, sublingual, buccal, rectal, vaginal, andintranasal. The term parenteral as used herein includes subcutaneousinjections, intravenous, intramuscular, intrasternal injection orinfusion techniques. Pharmaceutical compositions of the invention areformulated so as to allow the active ingredients contained therein to bebioavailable upon administration of the composition to a patient.Compositions that will be administered to a subject or patient take theform of one or more dosage units, where for example, a tablet may be asingle dosage unit, and a container of a compound of the invention inaerosol form may hold a plurality of dosage units. Actual methods ofpreparing such dosage forms are known, or will be apparent, to thoseskilled in this art; for example, see Remington: The Science andPractice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy andScience, 2000). The composition to be administered will, in any event,contain a therapeutically effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof, for treatmentof a disease or condition of interest in accordance with the teachingsof this invention.

A pharmaceutical composition of the invention may be in the form of asolid or liquid. In one aspect, the carrier(s) are particulate, so thatthe compositions are, for example, in tablet or powder form. Thecarrier(s) may be liquid, with the compositions being, for example, anoral oil, injectable liquid or an aerosol, which is useful in, forexample, inhalatory administration.

When intended for oral administration, the pharmaceutical composition ispreferably in either solid or liquid form, where semi-solid,semi-liquid, suspension and gel forms are included within the formsconsidered herein as either solid or liquid.

As a solid composition for oral administration, the pharmaceuticalcomposition may be formulated into a powder, granule, compressed tablet,pill, capsule, chewing gum, wafer or the like form. Such a solidcomposition will typically contain one or more inert diluents or ediblecarriers. In addition, one or more of the following may be present:binders such as carboxymethylcellulose, ethyl cellulose,microcrystalline cellulose, gum tragacanth or gelatin; excipients suchas starch, lactose or dextrins, disintegrating agents such as alginicacid, sodium alginate, Primogel, corn starch and the like; lubricantssuch as magnesium stearate or Sterotex; glidants such as colloidalsilicon dioxide; sweetening agents such as sucrose or saccharin; aflavoring agent such as peppermint, methyl salicylate or orangeflavoring; and a coloring agent.

When the pharmaceutical composition is in the form of a capsule, forexample, a gelatin capsule, it may contain, in addition to materials ofthe above type, a liquid carrier such as polyethylene glycol or oil.

The pharmaceutical composition may be in the form of a liquid, forexample, an elixir, syrup, solution, emulsion or suspension. The liquidmay be for oral administration or for delivery by injection, as twoexamples. When intended for oral administration, preferred compositioncontain, in addition to the present compounds, one or more of asweetening agent, preservatives, dye/colorant and flavor enhancer. In acomposition intended to be administered by injection, one or more of asurfactant, preservative, wetting agent, dispersing agent, suspendingagent, buffer, stabilizer and isotonic agent may be included.

The liquid pharmaceutical compositions of the invention, whether they besolutions, suspensions or other like form, may include one or more ofthe following adjuvants: sterile diluents such as water for injection,saline solution, preferably physiological saline, Ringer's solution,isotonic sodium chloride, fixed oils such as synthetic mono ordiglycerides which may serve as the solvent or suspending medium,polyethylene glycols, glycerin, propylene glycol or other solvents;antibacterial agents such as benzyl alcohol or methyl paraben;antioxidants such as ascorbic acid or sodium bisulfite; chelating agentssuch as ethylenediaminetetraacetic acid; buffers such as acetates,citrates or phosphates and agents for the adjustment of tonicity such assodium chloride or dextrose. The parenteral preparation can be enclosedin ampoules, disposable syringes or multiple dose vials made of glass orplastic. Physiological saline is a preferred adjuvant. An injectablepharmaceutical composition is preferably sterile.

A liquid pharmaceutical composition of the invention intended for eitherparenteral or oral administration should contain an amount of a compoundof the invention such that a suitable dosage will be obtained.Typically, this amount is at least 0.01% of a compound of the inventionin the composition. When intended for oral administration, this amountmay be varied to be between 0.1 and about 70% of the weight of thecomposition. Preferred oral pharmaceutical compositions contain betweenabout 4% and about 75% of the compound of the invention. Preferredpharmaceutical compositions and preparations according to the presentinvention are prepared so that a parenteral dosage unit contains between0.01 to 10% by weight of the compound prior to dilution of theinvention.

The pharmaceutical composition of the invention may be intended fortopical administration, in which case the carrier may suitably comprisea solution, emulsion, ointment or gel base. The base, for example, maycomprise one or more of the following: petrolatum, lanolin, polyethyleneglycols, bee wax, mineral oil, diluents such as water and alcohol, andemulsifiers and stabilizers. Thickening agents may be present in apharmaceutical composition for topical administration. If intended fortransdermal administration, the composition may include a transdermalpatch or iontophoresis device. Topical formulations may contain aconcentration of the compound of the invention from about 0.1 to about10% w/v (weight per unit volume).

The pharmaceutical composition of the invention may be intended forrectal administration, in the form, for example, of a suppository, whichwill melt in the rectum and release the drug. The composition for rectaladministration may contain an oleaginous base as a suitablenonirritating excipient. Such bases include, without limitation,lanolin, cocoa butter and polyethylene glycol.

The pharmaceutical composition of the invention may include variousmaterials, which modify the physical form of a solid or liquid dosageunit. For example, the composition may include materials that form acoating shell around the active ingredients. The materials that form thecoating shell are typically inert, and may be selected from, forexample, sugar, shellac, and other enteric coating agents.Alternatively, the active ingredients may be encased in a gelatincapsule.

The pharmaceutical composition of the invention in solid or liquid formmay include an agent that binds to the compound of the invention andthereby assists in the delivery of the compound. Suitable agents thatmay act in this capacity include a monoclonal or polyclonal antibody, aprotein or a liposome.

The pharmaceutical composition of the invention may consist of dosageunits that can be administered as an aerosol. The term aerosol is usedto denote a variety of systems ranging from those of colloidal nature tosystems consisting of pressurized packages. Delivery may be by aliquefied or compressed gas or by a suitable pump system that dispensesthe active ingredients. Aerosols of compounds of the invention may bedelivered in single phase, bi-phasic, or tri-phasic systems in order todeliver the active ingredient(s). Delivery of the aerosol includes thenecessary container, activators, valves, subcontainers, and the like,which together may form a kit. One of ordinary skill in the art, withoutundue experimentation may determine preferred aerosols.

The pharmaceutical compositions of the invention may be prepared bymethodology well known in the pharmaceutical art. For example, apharmaceutical composition intended to be administered by injection canbe prepared by combining a compound of the invention with sterile,distilled water so as to form a solution. A surfactant may be added tofacilitate the formation of a homogeneous solution or suspension.Surfactants are compounds that non-covalently interact with the compoundof the invention so as to facilitate dissolution or homogeneoussuspension of the compound in the aqueous delivery system.

The compounds of the invention, or their pharmaceutically acceptablesalts, are administered in a therapeutically effective amount, whichwill vary depending upon a variety of factors including the activity ofthe specific compound employed; the metabolic stability and length ofaction of the compound; the age, body weight, general health, sex, anddiet of the patient; the mode and time of administration; the rate ofexcretion; the drug combination; the severity of the particular disorderor condition; and the subject undergoing therapy. Generally, atherapeutically effective daily dose is (for a 70 kg mammal) from about0.001 mg/kg (i.e., 0.7 mg) to about 100 mg/kg (i.e., 7.0 gm); preferablya therapeutically effective dose is (for a 70 kg mammal) from about 0.01mg/kg (i.e., 7 mg) to about 50 mg/kg (i.e., 3.5 gm); more preferably atherapeutically effective dose is (for a 70 kg mammal) from about 1mg/kg (i.e., 70 mg) to about 25 mg/kg (i.e., 1.75 gm).

Compounds of the invention, or pharmaceutically acceptable derivativesthereof, may also be administered simultaneously with, prior to, orafter administration of one or more other therapeutic agents. Suchcombination therapy includes administration of a single pharmaceuticaldosage formulation which contains a compound of the invention and one ormore additional active agents, as well as administration of the compoundof the invention and each active agent in its own separatepharmaceutical dosage formulation. For example, a compound of theinvention and the other active agent can be administered to the patienttogether in a single oral dosage composition such as a tablet orcapsule, or each agent administered in separate oral dosageformulations. Where separate dosage formulations are used, the compoundsof the invention and one or more additional active agents can beadministered at essentially the same time, i.e., concurrently, or atseparately staggered times, i.e., sequentially; combination therapy isunderstood to include all these regimens.

Preparation of the Compounds of the Invention

The following Reaction Scheme illustrates methods to make compounds offormula (Ia), compounds of formula (Ib), compounds of formula (Ic) andcompounds of formula (Ib), as described above in the Summary of theInvention. It is understood that in the following Reaction Scheme,combinations of substituents and/or variables of the depicted formulaeare permissible only if such contributions result in stable compounds.

It will also be appreciated by those skilled in the art that in theprocesses described below the functional groups of intermediatecompounds may need to be protected by suitable protecting groups. Suchfunctional groups include hydroxy, amino, mercapto and carboxylic acid.Suitable protecting groups for hydroxy include trialkylsilyl ordiarylalkylsilyl (for example, t-butyldimethylsilyl,t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, andthe like. Suitable protecting groups for amino, amidino and guanidinoinclude benzyl, t-butoxycarbonyl, benzyloxycarbonyl, and the like.

Suitable protecting groups for mercapto include —C(O)—R″ (where R″ isalkyl, aryl or arylalkyl), p-methoxybenzyl, trityl and the like.Suitable protecting groups for carboxylic acids include alkyl, aryl orarylalkyl esters.

Protecting groups may be added or removed in accordance with standardtechniques, which are known to one of ordinary skill in the art and asdescribed herein.

The use of protecting groups is described in detail in Greene, T. W. andP. G. M. Wuts, Greene's Protective Groups in Organic Synthesis (1999),3rd Ed., Wiley. As one of skill in the art would appreciate, theprotecting group may also be a polymer resin such as a Wang resin, Rinkresin or a 2-chlorotrityl-chloride resin.

It will also be appreciated by those skilled in the art, although suchprotected derivatives of compounds of this invention may not possesspharmacological activity as such, they may be administered to a mammaland thereafter metabolized in the body to form compounds of theinvention which are pharmacologically active. Such derivatives maytherefore be described as “prodrugs”. All prodrugs of compounds of thisinvention are included within the scope of the invention.

It is understood that one of ordinary skill in the art would be able tomake the compounds of the invention by methods similar to the methodsdescribed herein or by methods known to one of ordinary skill in theart. It is also understood that one of ordinary skill in the art wouldbe able to make in a similar manner as described below other compoundsof formula (Ia), compounds of formula (Ib), compounds of formula (Ic)and compounds of formula (Id) not specifically illustrated below byusing the appropriate starting components and modifying the parametersof the synthesis as needed. In general, starting components may beobtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc.,Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. orsynthesized according to sources known to those skilled in the art (see,for example, Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, 5th edition (Wiley, December 2000)) or prepared as describedin this invention. ¹H NMR spectra were recorded in CDCl₃, DMSO-d₆,CD₃OD, Acetone-d₆ with trimethylsilane (TMS) as internal reference usingGemini 300 MHz instrument. Reagents and solvents were purchased fromcommercial sources and used without further purification. Flash columnchromatography was conducted using silica gel (230-400 mesh) under apositive pressure of nitrogen. LCMS spectra for purity and mass wererecorded using Waters LCMS instruments. Deionized water was used todilute the reactions and wash the products. Brine used was prepared bydissolving sodium chloride into deionized water to saturation point.

Preparation of Compounds of the Formula (Ia)

Compounds of formula (Ia), as set forth above in the Summary of theInvention, are prepared as described below in Reaction Scheme 1, wheren, m, R¹, R², R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), R⁴, R⁵, R⁶, R⁷,R⁸, R⁹ and R¹⁰ are as described above in the Summary of the Inventionfor compounds of formula (Ia); Pg is a nitrogen-protecting group andeach X is independently a leaving group, preferably halo, even morepreferably chloro. One of ordinary skill in the art would appreciatethat each X can be present in compounds of formula (Ba) or can beintroduced sequentially in order to react compounds of formula (Aa) andcompounds of formula (Ca). Skilled artisans would also appreciate thateach X may be the same or different leaving group.

Compounds of formula (Aa), compounds of formula (Ba) and compounds offormula (Da) are commercially available, for example, from Bioblocks orAldrich Chemical Co., or can be prepared by methods known to one skilledin the art.

In general, compounds of formula (Ia) are prepared by the method setforth in Reaction Scheme 1 above by first deprotecting the compound offormula (Aa) in the presence of an acid, preferably trifluoroaceticacid, in an aprotic solvent, preferably methylene chloride, at ambienttemperature. After removal of the volatiles, the product is then treatedwith an equimolar amount of a compound of formula (Ba) in the presenceof a base, preferably N,N-diisopropylethylamine, in a polar solvent,such as isopropanol, at a temperature of between about 50° C. and about70° C., preferably at about 60° C., for a period of time of betweenabout 4 hours and 20 hours, preferably for about 17 hours. The resultingreaction mixture is cooled to ambient temperature and the compound offormula (Ca) is isolated from the reaction mixture by standard isolationtechniques, such as evaporation of solvents and filtration.

The compound of formula (Ca) is then reacted with an excess molar amountof a compound of formula (Da) in a polar solvent, such as isopropanol,in the presence of an acid, preferably trifluoroacetic acid, at atemperature of between about 90° C. and about 110° C., preferably atabout 100° C., for a period of time of between about 4 hours and 20hours, preferably for about 12 hours, while stirring. The resultingreaction mixture is allowed to cool to ambient temperature and thesolvents are removed. The resulting residue is purified by standardpurification techniques, such as HPLC elution, to afford the compound offormula (Ia).

Preparation of Compounds of the Formula (Ib)

Compounds of formula (Ib), as set forth above in the Summary of theInvention, are prepared in a similar manner as described above inReaction Scheme 1 for compounds of formula (Ia), except that compoundsof formula (Ab):

where n, Pg, R¹, R⁴, R⁵, R⁶, R⁸ and R⁹ are as described above forcompounds of formula (Aa) in Reaction Scheme 1, are used in place ofcompounds of formula (Aa)) in Reaction Scheme 1 to produce the compoundsof formula (Ib) as set forth above in the Summary of the Invention.Compounds of formula (Ab) are commercially available or can be preparedby methods known to one skilled in the art.

Preparation of Compounds of the Formula (Ic)

Compounds of formula (Ic), as set forth above in the Summary of theInvention, are prepared in a similar manner as described above inReaction Scheme 1 for compounds of formula (Ia), except that compoundsof formula (Db):

where q, Y, R², R^(3e), R^(3f) and R^(3g) are as defined above in theSummary of the Invention for compounds of formula (Ic), are used inplace of compounds of formula (Da) to produce compounds of formula (Ic),as set forth above in the Summary of the Invention. Compounds of formula(Db) are commercially available or can be prepared by methods known toone skilled in the art.

Preparation of Compounds of the Formula (Id)

Compounds of formula (Id), as described above in the Summary of theInvention, are prepared in a similar manner as described above forcompounds of formula (Ia), except that compounds of formula (Dc):

where q, R², R^(3a), R^(3b), R^(3c), R^(3f) and R^(3g) are as definedabove in the Summary of the Invention for compounds of formula (Id), areused in place of compounds of formula (Da) to produce compounds offormula (Id) as set forth above in the Summary of the Invention.Compounds of formula (Dc) are commercially available or can be preparedby methods known to one skilled in the art.

All compounds of the invention which exist in free base or acid form canbe converted to their pharmaceutically acceptable salts by treatmentwith the appropriate inorganic or organic base or acid by methods knownto one of ordinary skill in the art. Salts of the compounds of theinvention can be converted to their free base or acid form by standardtechniques known to one skilled in the art.

The following specific Examples (for the preparation of the compounds ofthe invention) are provided as a guide to assist in the practice of theinvention, and are not intended as a limitation on the scope of theinvention. Where one or more NMR's are given for a particular compound,each NMR may represent a single stereoisomer, a non-racemic mixture ofstereoisomers or a racemic mixture of the stereoisomers of the compound.

Example 1(1R,2R,3S,5R)-2-(5-chloro-2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide

A. Commercially available(1R,2R,3S,5R)-(2,6,6-trimethyl-3-methylcarbamoyl-bicyclo[3.1.1]hept-2-yl)-carbamicacid tert-butyl ester (500 mg, 1.61 mmol) was dissolved in CH₂Cl₂ (4mL), followed by the addition of trifluoroacetic acid (TFA, 4 mL). Theresulting reaction mixture was stirred at ambient temperature for 3hours. The volatiles were evaporated under reduced pressure, the residuewas dissolved in isopropanol (6 mL). Then N,N-diisopropoylethylamine(0.8 mL, 4.83 mmol) and 2,5,6-trichloropyrimidine (295 mg, 1.61 mmol)were added, the reaction mixture was shaken at 60° C. for 17 hours.After cooling to ambient temperature, the volatiles were evaporatedunder reduced pressure. Water (10 mL) was added and the resulting whitesolid (compound of formula (C) was filtered (230 mg).

B. A sealed tube charged with the compound of formula (C) (50 mg, 0.14mmol), 4-[2-(1-pyrrolidinyl)ethoxy]-benzenamine (27 mg, 0.154 mmol), 5drops of TFA and isopropanol (1 mL) was shaken at 100° C. overnight.After cooling to ambient temperature, the volatiles were evaporatedunder reduced pressure. The residue was purified by HPLC eluting withacetonitrile—water to provide(1R,2R,3S,5R)-2-(5-chloro-2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide(Compound #1) (45 mg); ¹H NMR (300 MHz, CD₃OD) δ: 8.41 (brs, 1H), 8.32(s, 1H), 7.94 (s, 1H), 7.70 (s, 1H), 7.39 (d, J=8.7 Hz, 2H), 6.95 (d,J=8.7 Hz, 2H), 4.29 (d, J=4.8 Hz, 2H), 3.62 (d, J=4.8 Hz, 2H), 3.45 (m,3H), 3.30-3.06 (m, 2H), 2.79 (d, J=3.3 Hz, 3H), 2.20-1.95 (m, 7H), 1.70(s, 3H), 1.29 (s, 3H), 1.22 (d, J=9.9 Hz, 2H), 1.14 (s, 3H); LC-MS:purity: 100%; MS (m/e): 527.2 (MH+).

Example 2

In a similar manner as described above in Example 1 using appropriatelysubstituted reagents and starting materials, the following compounds offormula (Ia), compounds of formula (Ib), compounds of formula (Ic) andcompounds of formula (Id) were prepared. The number following eachcompound below refers to its number in Tables 1-4, as discussed in moredetail below.

-   (1R,2R,3S,5R)-2-(5-chloro-2-(4-morpholinophenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    Compound #2, ¹NMR (300 MHz, DMSO-d6) δ: 8.44 (d, J=4.2 Hz, 1H), 8.11    (d, J=4.2 Hz, 1H), 7.79 (s, 1H), 7.39 (d, J=8.7 Hz, 2H), 6.82 (d,    J=8.7 Hz, 2H), 3.71 (m, 4H), 3.31-3.01 (m, 9H), 2.65 (d, J=4.2 Hz,    3H), 1.63 (s, 3H), 1.23 (s, 3H), 1.07 (s, 3H), 1.05 (d, J=9.6 Hz,    2H); LC-MS: purity: 100%; MS (m/e): 499.0 (MH+);-   (1R,2R,3S,5R)-2-(5-chloro-2-(3-fluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    Compound #3, ¹H NMR (300 MHz, DMSO-d6) δ: 8.46 (brs, 1H), 8.25 (s,    1H), 8.10 (s, 1H), 7.86 (s, 1H), 7.79 (m, 1H), 7.23-7.06 (m, 2H),    4.23 (m, 2H), 3.1 (m, 13H), 2.66 (d, J=4.5 Hz, 3H), 1.89 (m, 6H),    1.68 (s, 3H), 1.24 (s, 3H), 1.12 (s, 3H), 1.10 (d, J=9.9 Hz, 2H);    LC-MS: purity: 100%; MS (m/e): 545.1 (MH+);-   (1R,2R,3S,5R)-2-(5-chloro-2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    Compound #4, ¹H NMR (300 MHz, CD₃OD) δ: 8.01 (s, 1H), 7.77 (s, 1H),    7.66 (m, 1H), 7.61 (m, 1H), 7.10 (m, 1H), 6.98 (m, 1H), 3.44 (m,    2H), 3.30-3.09 (m, 5H), 2.96 (s, 3H), 2.79 (s, 3H), 2.21-2.00 (m,    5H), 1.76 (s, 3H), 1.31 (s, 3H), 1.23 (d, J=10.8 Hz, 2H), 1.17 (s,    3H); LC-MS: purity: 100%; MS (m/e): 530.1 (MH+);-   (1R,2R,3S,5R)-2-(5-chloro-2-(3-chloro-4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    Compound #5, ¹H NMR (300 MHz, CD₃OD) δ: 8.18 (m, 1H), 8.04 (m, 1H),    7.77 (m, 1H), 7.24 (m, 1H), 7.07 (m, 1H), 3.41 (m, 2H), 3.30-3.11    (m, 5H), 2.94 (s, 3H), 2.79 (s, 3H), 2.15-1.99 (m, 5H), 1.80 (s,    3H), 1.31 (s, 3H), 1.22 (d, J=10.8 Hz, 2H), 1.19 (s, 3H); LC-MS:    purity: 100%; MS (m/e): 546.5 (MH+);-   (1R,2R,3S,5R)-2-(5-chloro-2-(3-sulfamoylphenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    Compound #6, ¹H NMR (300 MHz, CD₃OD) δ: 8.23-7.38 (m, 5H), 3.11 (m,    2H), 2.78 (s, 3H), 2.19-1.95 (m, 5H), 1.79 (s, 3H), 1.31 (s, 3H),    1.22 (d, J=9.6 Hz, 2H), 1.18 (s, 3H); LC-MS: purity: 100%; MS (m/e):    495.0 (MH+);-   (1R,2R,3S,5R)-2-(5-chloro-2-(4-(pyridin-4-ylmethyl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    Compound #7, ¹H NMR (300 MHz, CD₃OD) δ: 8.61-8.37 (m, 3H), 8.07 (m,    1H), 7.35 (m, 5H), 3.11 (m, 2H), 2.78 (s, 3H), 2.19-1.93 (m, 7H),    1.63 (s, 3H), 1.19 (s, 3H), 1.16 (d, J=9.6 Hz, 2H), 1.06 (s, 3H);    LC-MS: purity: 100%; MS (m/e): 505.0 (MH+);-   (1R,2R,3S,5R)-2-(5-chloro-2-(4-(2-methyl-2-(pyrrolidin-1-yl)propoxy)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    Compound #8, ¹H NMR (300 MHz, CD₃OD) δ: 8.11 (m, 1H), 7.95 (m, 1H),    7.70 (m, 1H), 7.42 (m, 2H), 6.98 (m, 2H), 4.09 (m, 2H), 3.10 (m,    4H), 2.78 (m, 3H), 2.11 (m, 10H), 1.71 (s, 3H), 1.51 (s, 6H), 1.30    (s, 3H), 1.20 (d, J=9.6 Hz, 2H), 1.15 (s, 3H); LC-MS: purity: 100%;    MS (m/e): 555.1 (MH+);-   (1R,2R,3S,5R)-2-(5-chloro-2-(4-(2-(cyclopentylamino)ethoxy)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    Compound #9, ¹H NMR (300 MHz, CD₃OD) δ: 7.72 (m, 1H), 7.40 (m, 2H),    6.94 (m, 2H), 4.25 (m, 2H), 3.46 (m, 2H), 3.10 (m, 4H), 2.79 (m,    3H), 2.14-1.85 (m, 11H), 1.68 (s, 3H), 1.30 (s, 3H), 1.20 (d, J=9.6    Hz, 2H), 1.14 (s, 3H); LC-MS: purity: 100%; MS (m/e): 541.1 (MH+);-   (1R,2R,3S,5R)-2-(5-chloro-2-(4-(4-cyclohexylpiperazine-1-carbonyl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    Compound #10, ¹H NMR (300 MHz, CD₃OD) δ: 8.04 (m, 1H), 7.81 (m, 1H),    7.70 (m, 2H), 7.40 (m, 2H), 3.93 (m, 2H), 3.20 (m, 10H), 2.79 (m,    3H), 2.16-1.95 (m, 9H), 1.78 (s, 3H), 1.42-1.39 (m, 4H), 1.33 (s,    3H), 1.24 (d, J=9.6 Hz, 2H), 1.19 (s, 3H); LC-MS: purity: 100%; MS    (m/e): 608.2 (MH+);-   (1R,2R,3S,5R)-2-(5-chloro-2-(4-(4-(4-fluorophenyl)piperazin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    Compound #11, ¹H NMR (300 MHz, CD₃OD) δ: 7.90 (m, 1H), 7.71 (m, 1H),    7.31 (m, 2H), 7.00 (m, 5H), 3.40-3.06 (m, 9H), 2.77 (m, 3H),    2.13-1.96 (m, 5H), 1.67 (s, 3H), 1.29 (s, 3H), 1.21 (d, J=9.6 Hz,    2H), 1.13 (s, 3H); LC-MS: purity: 100%; MS (m/e): 592.1 (MH+);-   (1R,2R,3S,5R)-2-(5-chloro-2-(4-(1-methylpiperidin-4-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    Compound #12, ¹H NMR (300 MHz, CD₃OD) δ: 8.43 (m, 1H), 8.07 (m, 2H),    7.73 (m, 1H), 7.47 (m, 2H), 7.16 (m, 2H), 3.62 (, 2H), 3.26-3.11 (m,    5H), 2.92 (s, 3H), 2.79 (m, 3H), 2.15-1.91 (m, 8H), 1.72 (s, 3H),    1.30 (s, 3H), 1.21 (d, J=9.6 Hz, 2H), 1.16 (s, 3H); LC-MS: purity:    100%; MS (m/e): 511.1 (MH+);-   (1R,2R,3S,5R)-2-(2-(4-(4-acetylpiperazin-1-yl)phenylamino)-5-chloropyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    Compound #13, ¹H NMR (300 MHz, CD₃OD) δ: 7.72 (m, 1H), 7.30 (m, 2H),    6.99 (m, 2H), 3.73 (m, 4H), 3.18 (m, 6H), 2.79 (m, 3H), 2.15 (s,    3H), 2.13-1.98 (m, 5H), 1.65 (s, 3H), 1.29 (s, 3H), 1.21 (d, J=9.6    Hz, 2H), 1.12 (s, 3H); LC-MS: purity: 100%; MS (m/e): 540.1 (MH+);-   (1R,2R,3S,5R)-2-(5-chloro-2-(4-(4-methylpiperazine-1-carbonyl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    Compound #14, ¹H NMR (300 MHz, CD₃OD) δ: 8.50 (m, 1H), 8.20 (m, 1H),    8.14 (m, 2H), 7.83 (m, 1H), 7.41 (m, 1H), 7.28 (m, 1H), 3.97 (m,    2H), 3.20-2.86 (m, 5H), 2.81 (m, 3H), 2.70 (s, 3H), 2.23-1.99 (m,    5H), 1.83 (s, 3H), 1.33 (s, 3H), 1.23 (d, J=9.6 Hz, 2H), 1.21 (s,    3H); LC-MS: purity: 100%; MS (m/e): 574.5 (MH+);-   (1R,2R,3S,5R)-2-(5-chloro-2-(4-chloro-3-(4-ethylpiperazin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    Compound #15, ¹H NMR (300 MHz, CD₃OD) δ: 8.12 (s, 1H), 8.03 (s, 1H),    7.76 (m, 1H), 7.41 (m, 2H), 7.27 (m, 1H), 3.42 (m, 9H), 3.12 (t,    J=7.2 Hz, 2H), 2.79 (m, 3H), 2.23-1.95 (m, 5H), 1.76 (s, 3H), 1.42    (t, J=7.2 Hz, 3H), 1.31 (s, 3H), 1.21 (d, J=9.6 Hz, 2H), 1.17 (s,    3H); LC-MS: purity: 100%; MS (m/e): 560.1 (MH+);-   (1R,2R,3S,5R)-2-(2-(3-(4-acetylpiperazin-1-yl)-4-chlorophenylamino)-5-chloropyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    Compound #16, ¹H NMR (300 MHz, CD₃OD) δ: 8.18 (s, 1H), 8.01 (m, 1H),    7.76 (s, 1H), 7.24 (m, 3H), 3.79 (m, 4H), 3.25-2.96 (m, 5H), 2.79    (m, 3H), 2.15 (s, 3H), 2.13-1.95 (m, 5H), 1.75 (s, 3H), 1.30 (s,    3H), 1.21 (d, J=9.6 Hz, 2H), 1.16 (s, 3H); LC-MS: purity: 100%; MS    (m/e): 574.5 (MH+);-   (1R,2R,3S,5R)-2-(2-(benzyloxy)ethyl)-2-(5-chloro-2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-ylamino)-6,6-dimethylbicyclo[3.1.1]heptane-3-carboxamide,    Compound #17, ¹H NMR (300 MHz, CD₃OD) δ: 9.20 (s, 1H), 8.11 (m, 1H),    7.78 (m, 1H), 7.53 (m, 1H), 7.30-6.95 (m, 5H), 4.35 (s, 2H), 3.71    (m, 1H), 3.45 (m, 13H), 2.95 (m, 3H), 2.40-1.75 (m, 4H), 1.31 (s,    3H), 1.27 (d, J=9.6 Hz, 2H), 1.18 (s, 3H); LC-MS: purity: 100%; MS    (m/e): 636.2 (MH+);-   (1R,2R,3S,5R)-2-(2-(3-(4-(methoxycarbonyl)piperazin-1-yl)-4-chlorophenylamino)-5-chloropyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    Compound #18, ¹H NMR (300 MHz, CD₃OD) δ: 8.18 (s, 1H), 8.01 (m, 1H),    7.79 (m, 1H), 7.28 (m, 3H), 3.71 (s, 3H), 3.63 (m, 4H), 3.28-3.02    (m, 5H), 2.79 (m, 3H), 2.21-1.95 (m, 5H), 1.75 (s, 3H), 1.30 (s,    3H), 1.21 (d, J=9.6 Hz, 2H), 1.16 (s, 3H); LC-MS: purity: 100%; MS    (m/e): 590.5 (MH+);-   (1R,2R,3S,5R)-2-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-ylamino)-2-(2-hydroxyethyl)-6,6-dimethylbicyclo[3.1.1]heptane-3-carboxamide,    Compound #19, ¹H NMR (300 MHz, CD₃OD) δ: 8.20 (s, 1H), 7.60 (m, 1H),    7.41 (m, 1H), 7.08 (m, 2H), 6.03 (m, 1H), 3.72 (m, 2H), 3.49 (m,    2H), 3.35-3.30 (m, 6H), 2.85 (m, 3H), 2.40-1.85 (m, 6H), 1.29 (s,    3H), 1.21 (d, J=9.6 Hz, 2H), 1.16 (s, 3H); LC-MS: purity: 100%; MS    (m/e): 512.6 (MH+);-   (1R,2R,3S,5R)-2-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    Compound #20, ¹H NMR (300 MHz, CD₃OD) δ: 8.23 (m, 2H), 7.60 (m, 1H),    7.48 (m, 1H), 7.09 (m, 2H), 3.30-3.00 (m, 9H), 2.87 (s, 3H), 2.78    (m, 3H), 2.27-1.95 (m, 5H), 1.63 (s, 3H), 1.29 (s, 3H), 1.20 (d,    J=9.6 Hz, 2H), 1.14 (s, 3H); LC-MS: purity: 100%; MS (m/e): 496.6    (MH+);-   (1S,2S,3R,5S)-2-(5-chloro-2-(4-morpholinophenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    Compound #21, ¹NMR (300 MHz, DMSO-d6) δ: 8.75 (m, 1H), 8.42 (m, 1H),    8.18 (m, 2H), 7.78 (m, 1H), 7.41 (m, 1H), 6.83 (m, 2H), 3.71 (m,    4H), 3.10-3.00 (m, 6H), 2.64 (m, 3H), 2.05-1.87 (m, 4H), 1.63 (s,    3H), 1.23 (s, 3H), 1.10 (s, 3H), 1.08 (d, J=9.6 Hz, 2H); LC-MS:    purity: 100%; MS (m/e): 499.2 (MH+);-   (1S,2S,3R,5S)-2-(5-chloro-2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    Compound #22, ¹NMR (300 MHz, DMSO-d6) δ: 8.77 (m, 1H), 8.42 (m, 1H),    8.13 (m, 2H), 7.78 (m, 1H), 7.44 (m, 1H), 6.79 (m, 2H), 4.02 (m,    2H), 3.16-2.87 (m, 11H), 2.63 (m, 3H), 2.04-1.97 (m, 5H), 1.63 (s,    3H), 1.22 (s, 3H), 1.07 (s, 3H), 1.05 (d, J=9.6 Hz, 2H); LC-MS:    purity: 100%; MS (m/e): 527.2 (MH+);-   (1S,2S,3R,5S)-2-(5-chloro-2-(3-fluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    Compound #23, ¹NMR (300 MHz, DMSO-d6) δ: 8.46 (m, 1H), 8.25 (m, 1H),    8.10 (m, 2H), 7.86 (m, 1H), 7.41 (m, 1H), 7.23-7.05 (m, 2H), 4.23    (m, 2H), 3.29 (m, 8H), 2.66 (m, 3H), 2.07-1.98 (m, 8H), 1.68 (s,    3H), 1.24 (s, 3H), 1.11 (s, 3H), 1.06 (d, J=9.3 Hz, 2H); LC-MS:    purity: 100%; MS (m/e): 545.2 (MH+);-   (1R,2R,3S,5R)-2-(5-chloro-2-(2,2-difluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-ylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    Compound #24, ¹H NMR (300 MHz, CD₃OD) δ: 8.23 (m, 1H), 8.09 (m, 1H),    7.80 (m, 1H), 3.11 (m, 2H), 2.79 (s, 3H), 2.19-1.93 (m, 5H), 1.77    (s, 3H), 1.32 (s, 3H), 1.19 (s, 3H), 1.18 (d, J=9.6 Hz, 2H); LC-MS:    purity: 100%; MS (m/e): 522.9 (MH+);-   (1R,2R,3S,5R)-2-(2-(1H-indol-5-ylamino)-5-chloropyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    Compound #26, ¹H NMR (300 MHz, CD₃OD) δ: 8.18 (m, 1H), 7.68 (m, 1H),    7.60 (m, 1H), 7.34 (m, 1H), 7.24 (m, 1H), 7.01 (m, 1H), 6.40 (m,    1H), 3.10 (m, 2H), 2.79 (s, 3H), 2.11-1.94 (m, 4H), 1.39 (m, 4H),    1.63 (m, 3H), 1.14 (s, 3H), 1.12 (d, J=9.6 Hz, 2H), 1.05 (s, 3H);-   LC-MS: purity: 100%; MS (m/e): 453.2 (MH+);-   (1R,2R,3S,5R)-2-(5-chloro-2-(1-(2-(dimethylamino)ethyl)indolin-5-ylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    Compound #27; ¹H NMR (300 MHz, CD₃OD) δ: 8.09 (m, 1H), 7.78 (m, 1H),    7.20 (m, 1H), 6.66 (m, 1H), 3.57-3.35 (m, 5H), 3.06 (m, 4H), 2.97    (s, 3H), 2.87 (s, 3H), 2.78 (s, 3H), 2.14-1.99 (m, 5H), 1.68 (s,    3H), 1.28 (s, 3H), 1.16 (d, J=9.6 Hz, 2H), 1.14 (s, 3H); LC-MS:    purity: 100%; MS (m/e): 526.2 (MH+);-   (1R,2R,3S,5R)-2-(5-chloro-2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-ylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    Compound #28, ¹H NMR (300 MHz, CD₃OD) δ: 7.73 (m, 1H), 7.36 (m, 1H),    6.96 (m, 1H), 6.78 (m, 1H), 4.54 (m, 2H), 3.11 (m, 2H), 2.79 (m,    3H), 2.15-1.99 (m, 5H), 1.74 (s, 3H), 1.31 (s, 3H), 1.29 (d, J=9.6    Hz, 2H), 1.16 (s, 3H);-   LC-MS: purity: 100%; MS (m/e): 482.2 (MH+);-   (1R,2R,3S,5R)-2-(5-chloro-2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)pyrimidin-4-ylamino)-2,6,6-trimethylbicyclo[3.1.1]heptane-3-carboxamide,    compound #29, ¹H NMR (300 MHz, CD₃OD) δ: 8.08 (m, 1H), 7.72 (m, 1H),    7.39 (d, J=8.7 Hz, 2H), 6.96 (d, J=8.7 Hz, 2H), 4.31 (m, 2H), 3.65    (m, 2H), 3.45-3.20 (m, 7H), 2.14-2.10 (m, 9H), 1.70 (s, 3H), 1.29    (s, 3H), 1.27 (d, J=9.6 Hz, 2H), 1.15 (s, 3H); LC-MS: purity: 100%;    MS (m/e): 513.2 (MH+);-   (1R,2R,3S,5R)-2-(5-chloro-2-(3-fluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)pyrimidin-4-ylamino)-2,6,6-trimethylbicyclo[3.1.1]heptane-3-carboxamide,    compound #30, ¹H NMR (300 MHz, CD₃OD) δ: 7.50 (m, 2H), 7.76 (m, 1H),    7.54 (m, 1H), 7.10 (m, 2H), 4.34 (m, 2H), 3.66 (m, 2H), 3.49-3.22    (m, 7H), 2.14-2.00 (m, 9H), 1.79 (s, 3H), 1.31 (s, 3H), 1.27 (d,    J=9.6 Hz, 2H), 1.23 (s, 3H); LC-MS: purity: 100%; MS (m/e): 531.2    (MH+);-   (1R,2R,3S,5R)-2-(5-chloro-2-(3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    compound #31, ¹H NMR (300 MHz, CD₃OD) δ: 8.11 (m, 2H), 7.75 (m, 1H),    7.68 (m, 1H), 7.01 (m, 2H), 3.44 (m, 2H), 3.12 (m, 8H), 2.79 (m,    3H), 2.75 (s, 3H), 2.69 (m, 4H), 2.16-2.00 (m, 8H), 1.80 (m, 2H),    1.74 (s, 3H), 1.30 (s, 3H), 1.21 (d, J=9.6 Hz, 2H), 1.16 (s, 3H);    LC-MS: purity: 100%; MS (m/e): 613.3 (MH+);-   (1R,2R,3S,5R)-2-(5-chloro-2-(3-fluoro-4-(4-(diethylamino)piperidin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    compound #32, ¹H NMR (300 MHz, CD₃OD) δ: 8.06 (m, 1H), 7.77 (m, 1H),    7.66 (m, 1H), 7.01 (m, 2H), 3.53 (m, 2H), 3.15 (m, 8H), 2.80 (m,    7H), 2.14-1.96 (m, 11H), 1.74 (s, 3H), 1.38 (t, J=7.2 Hz, 4H), 1.30    (s, 3H), 1.21 (d, J=11.7 Hz, 2H), 1.16 (s, 3H); LC-MS: purity: 100%;    MS (m/e): 586.2 (MH+);-   (1R,2R,3S,5R)-2-(5-chloro-2-(4-(2-((cyclopentyl)(methyl)amino)ethoxy)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    compound #33, ¹H NMR (300 MHz, CD₃OD) δ: 7.74 (m, 1H), 7.38 (d,    J=9.0 Hz, 2H), 7.00 (d, J=9.0 Hz, 2H), 4.35 (m, 2H), 3.78 (m, 2H),    3.11 (m, 2H), 2.97 (s, 3H), 2.79 (m, 3H), 2.19-1.74 (m, 13H), 1.66    (m, 2H), 1.29 (s, 3H), 1.18 (d, J=10.5 Hz, 2H), 1.13 (s, 3H); LC-MS:    purity: 100%; MS (m/e): 555.1 (MH+);-   (1R,2R,3S,5R)-2-(5-fluoro-2-(3-chloro-4-(4,4-difluoropipendin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    compound #34, ¹H NMR (300 MHz, CD₃OD) δ: 8.00 (m, 1H), 7.98 (m, 1H),    7.64 (m, 1H), 7.13 (m, 1H), 7.07 (m, 1H), 4.35 (m, 2H), 3.12 (m,    5H), 2.79 (m, 3H), 2.22-1.84 (m, 9H), 1.78 (s, 3H), 1.32 (s, 3H),    1.23 (d, J=10.5 Hz, 2H), 1.19 (s, 3H); LC-MS: purity: 100%; MS    (m/e): 551.2 (MH+);-   (1R,2R,3S,5R)-2-(5-fluoro-2-(3-fluoro-4-(4,4-difluoropiperidin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    compound #35, ¹H NMR (300 MHz, CD₃OD) δ: 7.97 (m, 1H), 7.58 (m, 2H),    6.99 (m, 1H), 4.35 (m, 2H), 3.12 (m, 5H), 2.78 (m, 3H), 2.22-1.84    (m, 9H), 1.74 (s, 3H), 1.32 (s, 3H), 1.23 (d, J=9.9 Hz, 2H), 1.17    (s, 3H); LC-MS: purity: 100%; MS (m/e): 535.2 (MH+);-   (1R,2R,3S,5R)-2-(5-fluoro-2-(3-chloro-4-(4-methylsulfonylpiperazin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    compound #36, ¹H NMR (300 MHz, CD₃OD) δ: 8.00 (m, 1H), 7.65 (m, 1H),    7.18 (m, 1H), 7.07 (m, 1H), 7.07 (m, 1H), 3.39 (m, 4H), 3.08 (m,    5H), 2.90 (s, 3H), 2.78 (s, 3H), 2.13-1.99 (m, 5H), 1.79 (s, 3H),    1.32 (s, 3H), 1.24 (d, J=10.5 Hz, 2H), 1.19 (s, 3H); LC-MS: purity:    100%; MS (m/e): 594.2 (MH+);-   (1R,2R,3S,5R)-2-(5-fluoro-2-(3-trifluoromethyl-4-(4-methylsulfonylpiperazin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    compound #37, ¹H NMR (300 MHz, CD₃OD) δ: 8.11 (m, 1H), 8.03 (m, 1H),    7.66 (m, 1H), 7.55 (m, 1H), 7.42 (m, 1H), 3.24-2.98 (m, 9H), 2.89    (s, 3H), 2.78 (m, 3H), 2.15-1.99 (m, 5H), 1.76 (s, 3H), 1.28 (s,    3H), 1.24 (d, J=9.9 Hz, 2H), 1.17 (s, 3H); LC-MS: purity: 100%; MS    (m/e): 627.2 (MH+);-   (1R,2R,3S,5R)-2-(5-fluoro-2-(3-chloro-4-(4-acetylpiperazin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    compound #38, ¹H NMR (300 MHz, CD₃OD) δ: 8.00 (m, 1H), 7.65 (m, 1H),    7.16 (m, 1H), 7.03 (m, 1H), 3.74 (m, 4H), 3.12-2.90 (m, 5H), 2.79    (s, 3H), 2.15 (s, 3H), 2.13-1.98 (m, 5H), 1.79 (s, 3H), 1.32 (s,    3H), 1.24 (d, J=10.5 Hz, 2H), 1.19 (s, 3H); LC-MS: purity: 100%; MS    (m/e): 558.2 (MH+);-   (1R,2R,3S,5R)-2-(5-fluoro-2-(3-trifluoromethyl-4-(4-acetylpiperazin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    compound #39, ¹H NMR (300 MHz, CD₃OD) δ: 8.11 (m, 2H), 7.67 (m, 1H),    7.51 (m, 1H), 7.38 (m, 1H), 3.72 (m, 4H), 3.25-2.82 (m, 5H), 2.79    (m, 3H), 2.15 (s, 3H), 2.13-1.98 (m, 5H), 1.76 (s, 3H), 1.28 (s,    3H), 1.24 (d, J=10.5 Hz, 2H), 1.17 (s, 3H); LC-MS: purity: 100%; MS    (m/e): 592.2 (MH+);-   (1R,2R,3S,5R)-2-(5-fluoro-2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    compound #40, ¹H NMR (300 MHz, CD₃OD) δ: 8.60 (m, 2H), 8.07 (m, 1H),    7.64 (m, 1H), 7.38 (m, 2H), 6.98 (m, 2H), 4.35 (m, 2H), 3.66 (m,    2H), 3.18 (m, 5H), 2.78 (m, 3H), 2.30-1.99 (m, 9H), 1.66 (s, 3H),    1.30 (s, 3H), 1.24 (d, J=10.5 Hz, 2H), 1.14 (s, 3H); LC-MS: purity:    100%; MS (m/e): 511.2 (MH+);-   (1R,2R,3S,5R)-2-(5-chloro-2-(4-(4-(2-hydroxyethyl)piperazin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    compound #41, ¹H NMR (300 MHz, CD₃OD) δ: 8.24 (m, 1H), 7.99 (m, 1H),    7.70 (m, 1H), 7.38 (m, 2H), 6.97 (m, 2H), 3.89 (m, 2H), 3.37-3.07    (m, 10H), 2.78 (m, 3H), 2.37-1.89 (m, 5H), 1.70 (s, 3H), 1.30 (s,    3H), 1.21 (d, J=10.5 Hz, 2H), 1.15 (s, 3H); LC-MS: purity: 100%; MS    (m/e): 542.2 (MH+);-   (1R,2R,3S,5R)-2-(5-methyl-2-(4-(4-(2-hydroxyethyl)piperazin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    compound #42, ¹H NMR (300 MHz, CD₃OD) δ: 9.20 (m, 1H), 8.30 (m, 2H),    7.37 (m, 1H), 7.23 (m, 2H), 7.05 (m, 2H), 3.82 (m, 2H), 3.32-3.12    (m, 10H), 2.79 (m, 3H), 2.26-2.05 (m, 5H), 2.20 (s, 3H), 1.60 (s,    3H), 1.27 (s, 3H), 1.12 (m, 5H); LC-MS: purity: 100%; MS (m/e):    522.3 (MH+);-   (1R,2R,3S,5R)-2-(5-methyl-2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    compound #43, ¹H NMR (300 MHz, CD₃OD) δ: 9.44 (m, 1H), 8.10 (m, 2H),    7.39 (m, 2H), 7.09 (m, 2H), 3.45-3.05 (m, 8H), 2.95 (s, 3H), 2.79    (m, 3H), 2.26-1.98 (m, 8H), 1.62 (s, 3H), 1.27 (s, 3H), 1.14 (m,    5H); LC-MS: purity: 100%; MS (m/e): 510.2 (MH+);-   (1R,2R,3S,5R)-2-(5-methyl-2-(3-fluoro-4-(4,4-difluoropiperidin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    compound #44, ¹H NMR (300 MHz, CD₃OD) δ: 9.28 (m, 1H), 7.45-7.00 (m,    4H), 3.22 (m, 4H), 2.79 (m, 3H), 2.17-2.01 (m, 9H), 2.20 (s, 3H),    1.61 (s, 3H), 1.27 (s, 3H), 1.14 (m, 5H); LC-MS: purity: 100%; MS    (m/e): 531.2 (MH+);-   (1R,2R,3S,5R)-2-(5-chloro-2-((3,4-dihydro-4-(2-(diethylamino)ethyl)-2H-benzo[b][1,4]oxazin-7-yl)amino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    compound #45, ¹H NMR (300 MHz, CD₃OD) δ: 8.50 (m, 1H), 8.09 (m, 1H),    7.77 (m, 1H), 7.05 (m, 1H), 6.90 (m, 2H), 4.23 (m, 2H), 3.32-3.06    (m, 10H), 2.79 (m, 3H), 2.23-1.95 (m, 5H), 1.68 (s, 3H), 1.36 (t,    J=7.2 Hz, 6H), 1.30 (s, 3H), 1.15 (m, 5H); LC-MS: purity: 100%; MS    (m/e): 570.2 (MH+);-   (1R,2R,3S,5R)-2-(5-fluoro-2-((3,4-dihydro-4-(2-(diethylamino)ethyl)-2H-benzo[b][1,4]oxazin-7-yl)amino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    compound #46, ¹H NMR (300 MHz, CD₃OD) δ: 8.61 (m, 1H), 8.06 (m, 1H),    7.69 (m, 1H), 6.93 (m, 1H), 6.78 (m, 2H), 4.27 (m, 2H), 3.68 (m,    2H), 3.39 (m, 7H), 3.12 (m, 2H), 2.78 (m, 3H), 2.22-1.96 (m, 4H),    1.65 (s, 3H), 1.36 (t, J=7.2 Hz, 6H), 1.31 (s, 3H), 1.15 (m, 5H);    LC-MS: purity: 100%; MS (m/e): 554.2 (MH+);-   (1R,2R,3S,5R)-2-(5-chloro-2-((3,4-dihydro-4-(2-(dimethylamino)ethyl)-2H-benzo[b][1,4]oxazin-7-yl)amino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    compound #47, ¹H NMR (300 MHz, CD₃OD) δ: 8.14 (m, 2H), 7.70 (m, 1H),    7.23 (m, 1H), 6.83 (m, 1H), 6.73 (m, 1H), 4.47 (m, 2H), 3.96 (m,    2H), 3.62 (m, 2H), 3.18 (m, 2H), 2.95 (s, 6H), 2.79 (m, 3H),    2.21-1.96 (m, 5H), 1.68 (s, 3H), 1.31 (s, 3H), 1.17 (m, 5H); LC-MS:    purity: 100%; MS (m/e): 542.2 (MH+);-   (1R,2R,3S,5R)-2-(5-fluoro-2-((3,4-dihydro-4-(2-(dimethylamino)ethyl)-2H-benzo[b][1,4]oxazin-7-yl)amino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    compound #48, ¹H NMR (300 MHz, CD₃OD) δ: 8.18 (m, 1H), 7.59 (m, 1H),    7.15 (m, 1H), 6.76 (m, 2H), 4.30 (m, 2H), 3.59 (m, 2H), 3.38 (m,    2H), 3.16 (m, 2H), 2.96 (s, 6H), 2.78 (m, 3H), 2.21-1.95 (m, 5H),    1.72 (s, 3H), 1.32 (s, 3H), 1.21 (d, J=10.5 Hz, 2H), 1.16 (m, 3H);    LC-MS: purity: 100%; MS (m/e): 526.2 (MH+);-   (1R,2R,3S,5R)-2-(5-methyl-2-((3,4-dihydro-4-(2-(dimethylamino)ethyl)-2H-benzo[b][1,4]oxazin-7-yl)amino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    compound #49, ¹H NMR (300 MHz, CD₃OD) δ: 8.30 (m, 1H), 7.38 (m, 1H),    6.95-6.73 (m, 3H), 4.27 (m, 2H), 3.63 (m, 2H), 3.38 (m, 2H), 3.18    (m, 2H), 2.95 (s, 6H), 2.79 (m, 3H), 2.20-2.08 (m, 5H), 2.02 (s,    3H), 1.65 (s, 3H), 1.30 (s, 3H), 1.15 (m, 5H); LC-MS: purity: 100%;    MS (m/e): 522.3 (MH+);-   (1R,2R,3S,5R)-2-(5-chloro-2-((3,4-dihydro-4-(2-(dimethylamino)ethyl)-2H-benzo[b][1,4]oxazin-6-yl)amino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    compound #50, ¹H NMR (300 MHz, CD₃OD) δ: 8.06 (m, 1H), 7.78 (m, 1H),    6.88 (m, 1H), 6.73 (m, 2H), 4.25 (m, 2H), 3.63 (m, 2H), 3.40 (m,    2H), 3.12 (m, 2H), 2.97 (s, 6H), 2.79 (m, 3H), 2.16-2.00 (m, 5H),    1.68 (s, 3H), 1.30 (s, 3H), 1.14 (m, 5H); LC-MS: purity: 100%; MS    (m/e): 542.2 (MH+);-   (1R,2R,3S,5R)-2-(5-fluoro-2-((3,4-dihydro-4-(2-(dimethylamino)ethyl)-2H-benzo[b][1,4]oxazin-6-yl)amino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    compound #51, ¹H NMR (300 MHz, CD₃OD) δ: 8.06 (m, 1H), 7.63 (m, 1H),    6.88 (m, 1H), 6.78 (m, 3H), 4.25 (m, 2H), 3.64 (m, 2H), 3.38 (m,    2H), 3.13 (m, 2H), 3.11 (s, 6H), 2.78 (m, 3H), 2.20-2.01 (m, 5H),    1.66 (s, 3H), 1.31 (s, 3H), 1.15 (m, 5H); LC-MS: purity: 100%; MS    (m/e): 526.2 (MH+);-   (1R,2R,3S,5R)-2-(5-trifluoromethyl-2-(3-fluoro-4-(4-(diethylamino)piperidin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    compound #52, ¹H NMR (300 MHz, CD₃OD) δ: 8.35 (m, 1H), 8.01 (m, 1H),    7.86 (m, 1H), 7.55 (m, 1H), 7.09-6.96 (m, 2H), 3.50 (m, 4H), 3.10    (m, 2H), 2.84 (m, 2H), 2.77 (m, 3H), 2.17-1.99 (m, 10H), 1.76 (s,    3H), 1.38 (m, 6H), 1.29 (s, 3H), 1.21 (d, J=10.5 Hz, 2H), 1.15 (m,    3H); LC-MS: purity: 100%; MS (m/e): 620.3 (MH+);-   (1R,2R,3S,5R)-2-(5-trifluoromethyl-2-((3,4-dihydro-4-(2-(diethylamino)ethyl)-2H-benzo[b][1,4]oxazin-7-yl)-amino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    compound #53, ¹H NMR (300 MHz, CD₃OD) δ: 8.38 (m, 1H), 8.17 (m, 1H),    7.96 (m, 1H), 7.81 (m, 1H), 7.26 (m, 1H), 6.89-6.74 (m, 2H), 4.52    (m, 2H), 4.27 (m, 2H), 3.90 (m, 2H), 3.73-3.58 (m, 4H), 3.12 (m,    2H), 2.77 (m, 3H), 2.13-2.10 (m, 5H), 1.76 (s, 3H), 1.36 (m, 6H),    1.30 (s, 3H), 1.23 (d, J=10.5 Hz, 2H), 1.15 (m, 3H); LC-MS: purity:    100%; MS (m/e): 604.2 (MH+);-   (1R,2R,3S,5R)-2-(5-chloro-2-(3-fluoro-4-(4-(4-methylpiperidin-1-yl)piperidin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    compound #54, ¹H NMR (300 MHz, CD₃OD) δ: 8.45 (m, 1H), 8.10 (m, 1H),    8.05 (m, 1H), 7.75 (m, 1H), 7.60 (m, 1H), 7.54 (m, 1H), 7.08-6.93    (m, 1H), 3.58 (m, 2H), 3.37-3.24 (m, 6H), 3.10 (m, 2H), 2.78 (m,    5H), 2.20-1.99 (m, 9H), 1.63 (m, 2H), 1.48 (m, 2H), 1.29 (s, 3H),    1.18 (d, J=10.5 Hz, 2H), 1.14 (m, 3H), 1.04 (d, J=6.3 Hz, 3H);    LC-MS: purity: 100%; MS (m/e): 612.2 (MH+);-   (1R,2R,3S,5R)-2-(5-fluoro-2-(3-fluoro-4-(4-(4-methylpiperidin-1-yl)piperidin-1-yl)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    compound #55, ¹H NMR (300 MHz, CD₃OD) δ: 8.57 (m, 1H), 7.74 (m, 1H),    7.34 (m, 1H), 7.05 (m, 2H), 3.57 (m, 2H), 3.37-3.24 (m, 6H), 3.12    (m, 2H), 2.80 (m, 5H), 2.16-1.98 (m, 9H), 1.45 (m, 2H), 1.30 (s,    3H), 1.22 (d, J=10.2 Hz, 2H), 1.17 (m, 3H), 1.04 (d, J=6.6 Hz, 3H);    LC-MS: purity: 100%; MS (m/e): 596.2 (MH+);-   (1R,2R,3S,5R)-2-(5-chloro-2-((3,4-dihydro-4-(2-(piperidin-1-yl)ethyl)-2H-benzo[b][1,4]oxazin-7-yl)amino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    compound #56, ¹H NMR (300 MHz, CD₃OD) δ: 8.10 (m, 1H), 7.73 (m, 1H),    7.16 (m, 1H), 6.81 (m, 3H), 4.82-4.40 (m, 8H), 3.83 (m, 4H), 2.78    (m, 3H), 2.25-1.82 (m, 11H), 1.74 (s, 3H), 1.31 (s, 3H), 1.23 (d,    J=10.5 Hz, 2H), 1.14 (m, 3H); LC-MS: purity: 100%; MS (m/e): 582.2    (MH+);-   (1R,2R,3S,5R)-2-(5-fluoro-2-((3,4-dihydro-4-(2-(piperidin-1-yl)ethyl)-2H-benzo[b][1,4]oxazin-7-yl)amino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    compound #57, ¹H NMR (300 MHz, CD₃OD) δ: 8.07 (m, 1H), 7.68 (m, 1H),    7.11 (m, 1H), 6.81 (m, 2H), 4.93-4.46 (m, 8H), 3.83 (m, 4H), 2.78    (m, 3H), 2.27-1.85 (m, 11H), 1.78 (s, 3H), 1.30 (s, 3H), 1.23 (d,    J=10.5 Hz, 2H), 1.15 (m, 3H); LC-MS: purity: 100%; MS (m/e): 566.2    (MH+);-   (1R,2R,3S,5R)-2-(5-chloro-2-((3,4-dihydro-4-(2-(morpholin-4-yl)ethyl)-2H-benzo[b][1,4]oxazin-7-yl)amino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    compound #58, ¹H NMR (300 MHz, CD₃OD) δ: 8.11 (m, 1H), 7.71 (m, 1H),    7.11 (m, 1H), 6.80 (m, 2H), 4.78 (m, 2H), 4.42 (m, 2H), 3.80 (m,    6H), 3.10-2.93 (m, 6H), 2.79 (m, 3H), 2.21-1.95 (m, 5H), 1.70 (s,    3H), 1.31 (s, 3H), 1.29 (d, J=10.5 Hz, 2H), 1.15 (m, 3H); LC-MS:    purity: 100%; MS (m/e): 584.1 (MH+);-   (1R,2R,3S,5R)-2-(5-fluoro-2-((3,4-dihydro-4-(2-(morpholin-4-yl)ethyl)-2H-benzo[b][1,4]oxazin-7-yl)amino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide,    compound #59, ¹H NMR (300 MHz, CD₃OD) δ: 8.051 (m, 1H), 7.68 (m,    1H), 6.83 (m, 2H), 4.78 (m, 2H), 3.90 (m, 6H), 3.20 (m, 6H), 2.79    (m, 3H), 2.25-2.01 (m, 7H), 1.65 (s, 3H), 1.31 (s, 3H), 1.15 (m,    5H); LC-MS: purity: 100%; MS (m/e): 568.2 (MH+);-   (1R,2R,3S,5R)-2-(5-chloro-2-((3,4-dihydro-4-(2-(dimethylamino)ethyl)-2H-benzo[b][1,4]oxazin-7-yl)amino)pyrimidin-4-ylamino)-N-(2-hydroxyethyl)-2,6,6-trimethylbicyclo[3.1.1]heptane-3-carboxamide,    compound #60, ¹H NMR (300 MHz, CD₃OD) δ: 8.17 (m, 1H), 7.69 (m, 1H),    7.23 (m, 1H), 6.85 (m, 1H), 6.71 (m, 1H), 4.65 (m, 2H), 4.44 (m,    2H), 3.94-3.61 (m, 6H), 2.94 (s, 6H), 2.69 (m, 2H), 2.16-1.99 (m,    5H), 1.76 (m, 3H), 1.31 (m, 3H), 1.20 (d, J=9.6 Hz, 2H), 1.15 (s,    3H); LC-MS: purity: 100%; MS (m/e): 572.2 (MH+);-   (1R,2R,3S,5R)-2-(5-chloro-2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)pyrimidin-4-ylamino)-N-cyclopropyl-2,6,6-trimethylbicyclo[3.1.1]heptane-3-carboxamide,    compound #61, ¹H NMR (300 MHz, CD₃OD) δ: 8.45 (m, 1H), 8.08 (m, 1H),    7.74 (m, 1H), 7.38 (m, 1H), 6.99 (m, 2H), 4.31 (m, 2H), 3.67 (m,    3H), 3.10 (m, 4H), 2.73 (m, 2H), 2.13-1.99 (m, 4H), 1.64 (s, 3H),    1.31 (m, 1H), 1.28 (s, 3H), 1.18 (d, J=10.8 Hz, 2H), 1.12 (s, 3H),    0.77 (m, 2H), 0.52 (m, 2H); LC-MS: purity: 100%; MS (m/e): 555.2    (MH+);-   (1R,2R,3S,5R)-2-(5-chloro-2-(3-fluoro-4-(4-(diethylamino)piperidin-1-yl)phenylamino)pyrimidin-4-ylamino)-N-cyclopropyl-2,6,6-trimethylbicyclo[3.1.1]heptane-3-carboxamide,    compound #62, ¹H NMR (300 MHz, CD₃OD) δ: 8.40 (m, 1H), 8.07 (m, 1H),    7.78 (m, 1H), 7.51 (m, 1H), 7.02 (m, 2H), 3.53 (m, 2H), 3.37 (m,    2H), 3.22 (m, 2H), 3.08 (m, 2H), 2.78 (m, 3H), 2.14-1.96 (m, 8H),    1.71 (s, 3H), 1.38 (t, J=7.5 Hz, 6H), 1.30 (s, 3H), 1.19 (d, J=10.2    Hz, 2H), 1.14 (s, 3H), 0.78 (m, 2H), 0.52 (m, 2H); LC-MS: purity:    100%; MS (m/e): 612.3 (MH+);-   (1R,2R,3S,5R)-2-(5-chloro-2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)pyrimidin-4-ylamino)-N-(1-methylethyl)-2,6,6-trimethylbicyclo[3.1.1]heptane-3-carboxamide,    compound #63, ¹H NMR (300 MHz, CD₃OD) δ: 8.39 (m, 1H), 8.17 (m, 1H),    8.02 (m, 1H), 7.70 (m, 1H), 7.40 (m, 2H), 6.96 (m, 2H), 4.30 (m,    2H), 4.03 (m, 1H), 3.64 (m, 2H), 3.22-3.10 (m, 4H), 2.13-1.99 (m,    8H), 1.70 (s, 3H), 1.30 (m, 4H), 1.21 (d, J=10.2 Hz, 2H), 1.19 (s,    3H), 1.17 (t, J=6.0 Hz, 6H); LC-MS: purity: 100%; MS (m/e): 555.2    (MH+); and-   (1R,2R,3S,5R)-2-(5-chloro-2-((3,4-dihydro-4-(2-(dimethylamino)ethyl)-2H-benzo[b][1,4]oxazin-7-yl)amino)pyrimidin-4-ylamino)-N-(1-methylethyl)-2,6,6-trimethylbicyclo[3.1.1]heptane-3-carboxamide,    compound #64, ¹H NMR (300 MHz, CD₃OD) δ: 8.32 (m, 1H), 8.02 (m, 1H),    7.68 (m, 1H), 7.170 (m, 1H), 6.76 (m, 2H), 4.26 (m, 2H), 4.03 (m,    1H), 3.57 (m, 2H), 3.57-3.11 (m, 7H), 2.93 (s, 6H), 2.14-1.98 (m,    5H), 1.74 (s, 3H), 1.30 (m, 4H), 1.17 (m, 9H); LC-MS: purity: 100%;    MS (m/e): 570.2 (MH+).

Testing of the Compounds of the Invention

The compounds of the invention were tested in the following assay fortheir ability to inhibit Axl activity.

Phospho-AKT in-Cell Western Assay Reagents and Buffers:

-   Cell culture plate: 96 well assay plate (Corning 3610), white, clear    bottom, tissue-culture treated.-   Cells: Hela cells.-   Starvation medium: For Axl stimulation: 0.5% FCS (fetal calf serum)    in DMEM, plus Axl/Fc (extracellular domain of AXL fused to    immunoglobulin Fc region) (R&D, 154-AL) 500 ng/mL.-   For EGF (epidermal growth factor) stimulation: 0.5% FCS in DMEM    (Dulbecco's modified Eagles medium).-   Poly-L-Lysine 0.01% solution (the working solution): 10 μg/ml,    dilute In PBS (phosphate buffered saline).-   Axl antibody cross-linking:    -   1^(st): Mouse anti-Axl (R&D, MAB154).    -   2^(nd): Biotin-SP-conjugated AffiniPure goat anti-mouse IgG        (H+L) (Jackson ImmunoResearch #115-065-003).-   Fixing buffer: 4% formaldehyde in PBS.-   Wash buffer: 0.1% TritonX-100 in PBS.-   Quenching buffer: 3% H₂O₂, 0.1% Azide in wash buffer, Azide and    hydrogen peroxide 1(H₂O₂) are added fresh.-   Blocking buffer: 5% BSA in TBST (tris buffered saline plus 0.1%    Tween 20).-   Primary antibody: Rabbit anti-human Phospho-Akt antibody (Cell    Signaling 9271): 1×250 diluted in blocking buffer.-   Secondary antibody: HRP (horse radish peroxidase)-conjugated Goat    anti-Rabbit secondary, stock solution: Jackson ImmunoResearch (Goat    anti-Rabbit HRP, #111-035-144) 1:1 diluted in glycerol, store at    −20° C. The working solution: 1×2000 dilution of stock in blocking    buffer.-   Chemiluminescent working solution (Pierce, 37030): SuperSignal ELISA    (enzyme linked immunosorbant assay) Pico Chemiluminescent substrate.-   Crystal Violet solution: Stock: 2.5% Crystal violet in methanol,    filtered and kept at ambient temperature. The working solution:    dilute the stock 1:20 with PBS immediately before use.-   10% SDS: working solution: 5% SDS (sodium dodecylsulfate), diluted    in PBS

Methods: Day 1:

A 96 well TC (tissue culture treated) plate was coated with 10 μg/mLpoly-L-Lysine at 37° C. for 30 min, washed twice with PBS, and air-driedfor 5 minutes before cells were added. Hela cells were seeded at 10,000cells/well and the cells were starved in 100 μL starvation mediumcontaining Axl/Fc for 24 hrs.

Day 2:

The cells were pre-treated with test compounds by adding 100 μL of 2×test compound to the starvation medium on the cells. The cells wereincubated at 37° C. for 1 hr before stimulation.

The cells were stimulated by Axl-antibody cross-linking as follows: A5×1^(st)/2^(nd) Axl antibody mixture was made (37.5 μg/mL 1^(st)/100μg/mL 2^(nd)) in starvation medium and nutated at 4° C. with thoroughmixing for 1-2 hours for clustering. The resulting mix was warmed to 37°C. 50 μL of 5×Axl 1^(st)/2^(nd) of antibody cluster was added to thecells and the cells were incubated at 37° C. for 5 min.

After 5 minutes stimulation, the plate was flicked to remove medium andthe plate was tapped onto paper towels. Formaldehyde (4.0% in PBS, 100μL) was added to fix the cells and the cells were incubated at ambienttemperature for 20 min without shaking.

The cells were washed with a plate washer buffer to remove theformaldehyde solution. The plate was flicked to removed excess washbuffer and tapped onto paper towels. Quenching buffer (100 μL) was addedto each well and the cells were incubated at ambient temperature for 20minutes without shaking.

The cells were washed with a plate washer buffer to remove the quenchingbuffer. Blocking buffer (100 μL) was added and the cells were incubatedat ambient temperature for at least an hour with gentle shaking.

The cells were washed with a plate washer buffer and diluted primaryantibody (50 μL) was added to each well (blocking buffer was added tothe negative control wells instead). The plates were incubated overnightat 4° C. with gentle shaking.

Day 3:

The wash buffer was removed, diluted secondary antibody (100 μL) wasadded, and the cells were incubated at ambient temperature for 1 hourwith gentle shaking. During the incubation, the chemiluminescent reagentwas brought to ambient temperature.

The secondary antibody was removed by washing the cells 1× with washbuffer, 1× with PBS by plate washer. The PBS was removed from the plateand the chemiluminescent reagent (80 μL: 40 μL A and 40 μL B) was addedto each well at ambient temperature.

The resulting chemiluminescence was read with a Luminomitor within 10minutes to minimize changes in signal intensity. After reading thechemiluminescence, the cells were washed 1× with wash buffer and 1× withPBS by plate washer. The plate was tapped onto paper towels to removeexcess liquid from wells and air-dried at ambient temperature for 5minutes.

Crystal Violet working solution (60 μL) was added to each well and thecells were incubated at ambient temperature for 30 min. The crystalviolet solution was removed, and the wells were rinsed with PBS, thenwashed 3× with PBS (200 μL) for 5 minutes each.

5% SDS solution (70 μL) was added to each well and the cells wereincubated on a shaker for 30 min at ambient temperature.

The absorbance was read at 590 nM on a Wallac photospec. The 590 nMreadings indicated the relative cell number in each well. This relativecell number was then used to normalize each luminescence reading.

The results of the ability of the compounds of the invention to inhibitAxl activity, when tested in the above assay, are shown in the followingTables 1-4 wherein the level of activity (i.e., the IC₅₀) for eachcompound is indicated in each Table. The compound numbers in the Tablesreferred to the compounds disclosed herein as being prepared by themethods disclosed herein:

TABLE 1

  (Ia) Cpd # n m R¹ R² R⁴ R⁵ R⁶ R⁷ R⁸ R⁹ R¹⁰ R^(3a) R^(3b) R^(3c) R^(3d)R^(3e) IC₅₀  1 0 1 H H H CH₃ CH₃ CH₃ CH₃ — Cl H H

H H A  2 0 1 H H H CH₃ CH₃ CH₃ CH₃ — Cl H H

H H B  3 0 1 H H H CH₃ CH₃ CH₃ CH₃ — Cl H H

F H A  4 0 1 H H H CH₃ CH₃ CH₃ CH₃ — Cl H H

F H A  5 0 1 H H H CH₃ CH₃ CH₃ CH₃ — Cl H H

F H A  6 0 1 H H H CH₃ CH₃ CH₃ CH₃ — Cl H H H S(O)₂NH₂ H NA  7 0 1 H H HCH₃ CH₃ CH₃ CH₃ — Cl H H

H H NA  8 0 1 H H H CH₃ CH₃ CH₃ CH₃ — Cl H H

H H A  9 0 1 H H H CH₃ CH₃ CH₃ CH₃ — Cl H H

H H A 10 0 1 H H H CH₃ CH₃ CH₃ CH₃ — Cl H H

H H A 11 0 1 H H H CH₃ CH₃ CH₃ CH₃ — H H H

H H D 12 0 1 H H H CH₃ CH₃ CH₃ CH₃ — Cl H H

H H A 13 0 1 H H H CH₃ CH₃ CH₃ CH₃ — Cl H H

H H B 14 0 1 H H H CH₃ CH₃ CH₃ CH₃ — Cl H H

Cl H A 15 0 1 H H H CH₃ CH₃ CH₃ CH₃ — Cl H H Cl

H B 16 0 1 H H H CH₃ CH₃ CH₃ CH₃ — Cl H H Cl

H B 17 0 1 H H H CH₃

CH₃ CH₃ — Cl H H

F H D 18 0 1 H H H CH₃ CH₃ CH₃ CH₃ — Cl H H Cl

H D 19 0 0 H H H CH₃

CH₃ CH₃ — — H H

F H D 20 0 0 H H H CH₃ CH₃ CH₃ CH₃ — — H H

F H NA 29 0 1 H H H H CH₃ CH₃ CH₃ — Cl H H

H H A 30 0 1 H H H H CH₃ CH₃ CH₃ — Cl H H

F H A 31 0 1 H H H CH₃ CH₃ CH₃ CH₃ — Cl H H

F H A 32 0 1 H H H CH₃ CH₃ CH₃ CH₃ — Cl H H

F H A 33 0 1 H H H CH₃ CH₃ CH₃ CH₃ — Cl H H

H H A 34 0 1 H H H CH₃ CH₃ CH₃ CH₃ — F H H

Cl H D 35 0 1 H H H CH₃ CH₃ CH₃ CH₃ — F H H

F H D 36 0 1 H H H CH₃ CH₃ CH₃ CH₃ — F H H

Cl H B 37 0 1 H H H CH₃ CH₃ CH₃ CH₃ — F H H

CF₃ H D 38 0 1 H H H CH₃ CH₃ CH₃ CH₃ — F H H

Cl H B 39 0 1 H H H CH₃ CH₃ CH₃ CH₃ — F H H

CF₃ H D 40 0 1 H H H CH₃ CH₃ CH₃ CH₃ — F H H

H H B 41 0 1 H H H CH₃ CH₃ CH₃ CH₃ — Cl H H

H H A 42 0 1 H H H CH₃ CH₃ CH₃ CH₃ — CH₃ H H

H H B 43 0 1 H H H CH₃ CH₃ CH₃ CH₃ — CH₃ H H

F H A 44 0 1 H H H CH₃ CH₃ CH₃ CH₃ — CH₃ H H

F H B 52 0 1 H H H CH₃ CH₃ CH₃ CH₃ — CF₃ H H

F H A 54 0 1 H H H CH₃ CH₃ CH₃ CH₃ — Cl H H

F H A 55 0 1 H H H CH₃ CH₃ CH₃ CH₃ — F H H

F H A 61 0 1 H H H

CH₃ CH₃ CH₃ — Cl H H

H H A 62 0 1 H H H

CH₃ CH₃ CH₃ — Cl H H

F H A 63 0 1 H H H

CH₃ CH₃ CH₃ — Cl H H

H H A IC₅₀ activity: A = <1 μM B = 1 to 10 μM C = >10 to 20 μM D = >20μM

TABLE 2

  (Ib) Cpd # n m R¹ R² R⁴ R⁵ R⁶ R⁷ R⁸ R⁹ R¹⁰ R^(3a) R^(3b) R^(3c) R^(3d)R^(3e) IC₅₀ 21 0 1 H H H CH₃ CH₃ CH₃ CH₃ — Cl H H

H H B 22 0 1 H H H CH₃ CH₃ CH₃ CH₃ — Cl H H

H H D 23 0 1 H H H CH₃ CH₃ CH₃ CH₃ — Cl H H

F H B IC₅₀ activity: A = <1 μM B = 1 to 10 μM C = >10 to 20 μM D = >20μM

TABLE 3

  (Ic) Cpd # Y n m q R¹ R² R⁴ R⁵ R⁶ R⁷ R⁸ R⁹ R¹⁰ R^(3b) R^(3e) R^(3f)R^(3g) IC₅₀ 24 ═N— 0 1 4 — 28 ═C(R^(3b))— 0 1 2 H H H CH₃ CH₃ CH₃ CH₃ —Cl H H H 3-oxo D 45 ═C(R^(3b))— 0 1 0 H H H CH₃ CH₃ CH₃ CH₃ — Cl H H

— A 46 ═C(R^(3b))— 0 1 0 H H H CH₃ CH₃ CH₃ CH₃ — F H H

— A 47 ═C(R^(3b))— 0 1 0 H H H CH₃ CH₃ CH₃ CH₃ — Cl H H

— A 48 ═C(R^(3b))— 0 1 0 H H H CH₃ CH₃ CH₃ CH₃ — F H H

— B 49 ═C(R^(3b))— 0 1 0 H H H CH₃ CH₃ CH₃ CH₃ — CH₃ H H

— B 50 ═C(R^(3b))— 0 1 0 H H H CH₃ CH₃ CH₃ CH₃ — Cl H H

— B 51 ═C(R^(3b))— 0 1 0 H H H CH₃ CH₃ CH₃ CH₃ — F H H

— B 53 ═C(R^(3b))— 0 1 0 H H H CH₃ CH₃ CH₃ CH₃ — CF₃ H H

— A 56 ═C(R^(3b))— 0 1 0 H H H CH₃ CH₃ CH₃ CH₃ — CI H H

— A 57 ═C(R^(3b))— 0 1 0 H H H CH₃ CH₃ CH₃ CH₃ — F H H

— A 58 ═C(R^(3b))— 0 1 0 H H H CH₃ CH₃ CH₃ CH₃ — Cl H H

— A 59 ═C(R^(3b))— 0 1 0 H H H CH₃ CH₃ CH₃ CH₃ — F H H

— B 60 ═C(R^(3b))— 0 1 0 H H H

CH₃ CH₃ CH₃ — Cl H H

— A 64 ═C(R^(3b))— 0 1 0 H H H

CH₃ CH₃ CH₃ — Cl H H

— A IC₅₀ activity: A = <1 μM B = 1 to 10 μM C = >10 to 20 μM D = >20 μM

TABLE 4

  (Id) Cpd # n m q R¹ R² R⁴ R⁵ R⁶ R⁷ R⁸ R⁹ R¹⁰ R^(3b) R^(3e) R^(3f)R^(3g) IC₅₀ 26 0 1 2 H H H CH₃ CH₃ CH₃ CH₃ — Cl H H H 2-3 double bond B27 0 1 0 H H H CH₃ CH₃ CH₃ CH₃ — Cl H H

— A IC₅₀ activity: A = <1 μM B = 1 to 10 μM C = >10 to 20 μM D = >20 μM

All of the U.S. patents, U.S. patent application publications, U.S.patent applications, foreign patents, foreign patent applications andnon-patent publications referred to in this specification and/or listedin the Application Data Sheet are incorporated herein by reference, intheir entireties.

From the foregoing it will be appreciated that, although specificembodiments of the invention have been described herein for purposes ofillustration, various modifications may be made without deviating fromthe spirit and scope of the invention. Accordingly, the invention is notlimited except as by the appended claims.

1. A compound of formula (Ib):

wherein: n is 0 to 7; m is 0 to 2; R¹, R², R⁴ and R⁵ are eachindependently hydrogen, alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, —R¹⁴—OR¹⁵, —C(O)R¹⁵ or —C(O)N(R¹¹)R¹²; or R⁴ and R⁵,together with the nitrogen to which they are attached, form anoptionally substituted N-heteroaryl or an optionally substitutedN-heterocyclyl; R^(3a), R^(3b), R^(3c), R^(3d) and R^(3e) are eachindependently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, cyano,nitro, optionally substituted aryl, optionally substituted aralkyl,optionally substituted aralkenyl, optionally substituted aralkynyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionallysubstituted cycloalkylalkynyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheterocyclylalkenyl, optionally substituted heterocyclylalkynyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heteroarylalkenyl, optionallysubstituted heteroarylalkynyl, —R¹⁷—OR¹⁶, —R¹⁷—OC(O)—R¹⁶, —R¹⁷—N(R¹⁶)₂,—R¹⁷—C(O)R¹⁶, —R¹⁷—C(O)OR¹⁶, —R¹⁷—C(O)N(R¹⁶)₂, —R¹⁷—O—R¹⁸—C(O)N(R¹⁶)₂,—R¹⁷—O—R¹⁸—(R¹⁶)₂, —R¹⁷—N(R¹⁶)C(O)OR¹⁶, —R¹⁷—N(R¹⁶)C(O)R¹⁶,—R¹⁷—N(R¹⁶)S(O)_(t)R¹⁶ (where t is 1 or 2), —R¹⁷—S(O)_(t)OR¹⁶ (where tis 1 or 2), —R¹⁷—S(O)_(p)R¹⁶ (where p is 0, 1 or 2), and—R¹⁷—S(O)_(t)N(R¹⁶)₂ (where t is 1 or 2), where each R¹⁶ isindependently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted heteroaryl or optionally substitutedheteroarylalkyl, each R¹⁷ is independently a direct bond or a straightor branched alkylene or alkenylene chain, and R¹⁵ is a straight orbranched alkylene or alkenylene chain; R⁶, R⁷ and R⁸ are eachindependently alkyl, haloalkyl, or —R¹³—OR¹⁵; each R⁹ and R¹⁰ isindependently alkyl, halo, haloalkyl, aryl or aralkyl; R¹¹ and R¹² areeach independently selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl,hydroxyalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionallysubstituted cycloalkylalkynyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheterocyclylalkenyl, optionally substituted heterocyclylalkynyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heteroarylalkenyl, optionallysubstituted heteroarylalkynyl, —R¹⁴—OR¹⁵, —R¹⁴—CN, —R¹⁴—NO₂,—R¹⁴—N(R¹⁵)₂, —R¹⁴—C(O)OR¹⁵ and —R¹⁴—C(O)N(R¹⁵)₂; optionally, R¹¹ andR¹², together with the nitrogen to which they are attached, form anoptionally substituted N-heteroaryl or an optionally substitutedN-heterocyclyl; R¹³ is independently selected from the group consistingof a direct bond, an optionally substituted straight or branchedalkylene chain, an optionally substituted straight or branchedalkenylene chain and an optionally substituted straight or branchedalkynylene chain; each R¹⁴ is independently selected from the groupconsisting of an optionally substituted straight or branched alkylenechain, an optionally substituted straight or branched alkenylene chainand an optionally substituted straight or branched alkynylene chain; andeach R¹⁵ is independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted aralkenyl, optionally substituted aralkynyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted cycloalkylalkenyl, optionally substitutedcycloalkylalkynyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substitutedheterocyclylalkenyl, optionally substituted heterocyclylalkynyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heteroarylalkenyl, andoptionally substituted heteroarylalkynyl; as an isolated stereoisomer ormixture thereof, or a pharmaceutically acceptable salt thereof.
 2. Thecompound of claim 1 wherein: n is 0 to 4; m is 0 to 1; R¹, R², R⁴ and R⁵are each independently hydrogen, alkyl, cycloalkylalkyl, —R¹⁴—OR¹⁵,—C(O)R¹⁵ or —C(O)N(R¹¹)R¹²; R^(3a), R^(3b), R^(3c), R^(3d) and R^(3e)are each independently selected from the group consisting of hydrogen,alkyl, halo, haloalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, —R¹⁷—OR¹⁶, —R¹⁷—N(R¹⁶)₂,—R¹⁷—C(O)R¹⁶, —R¹⁷—C(O)OR¹⁶, —R¹⁷—C(O)N(R¹⁶)₂, —R¹⁷—O—R¹⁸—C(O)N(R¹⁶)₂,—R¹⁷—O—R¹⁸—N(R¹⁶)₂, and —R¹⁷—S(O)_(t)N(R¹⁶)₂ (where t is 1 or 2), whereeach R¹⁶ is independently hydrogen, alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl or optionallysubstituted heteroarylalkyl, each R¹⁷ is independently a direct bond ora straight or branched alkylene or alkenylene chain, and R¹⁸ is astraight or branched alkylene or alkenylene chain; R⁶, R⁷ and R⁸ areeach independently alkyl, haloalkyl, or —R¹³—OR¹⁵; each R⁹ and R¹⁰ isindependently alkyl, halo, haloalkyl, aryl or aralkyl; R¹¹ and R¹² areeach independently selected from the group consisting of hydrogen,alkyl, haloalkyl, hydroxyalkyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, —R¹⁴—OR¹⁵, —R¹⁴—CN,—R¹⁴—NO₂, —R¹⁴—N(R¹⁵)₂, —R¹⁴—C(O)OR¹⁵ and —R¹⁴—C(O)N(R¹⁵)₂; R¹³ isindependently selected from the group consisting of a direct bond or anoptionally substituted straight or branched alkylene chain; each R¹⁴ isan optionally substituted straight or branched alkylene chain; and eachR¹⁵ is independently selected from the group consisting of hydrogen,alkyl, haloalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl, andoptionally substituted heteroarylalkyl.
 3. The compound of claim 2wherein: n is 0; m is 0 to 1; R¹, R², R⁴ and R⁵ are each independentlyhydrogen, alkyl, cycloalkylalkyl, or —R¹⁴—OR¹⁵; R^(3a), R^(3b), R^(3c),R^(3d) and R^(3e) are each independently selected from the groupconsisting of hydrogen, alkyl, halo, haloalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl, optionally substituted heteroarylalkyl,—R¹⁷—OR¹⁶, —R¹⁷—N(R¹⁶)₂, —R¹⁷—C(O)R¹⁶, —R¹⁷—C(O)OR¹⁶, —R¹⁷—C(O)N(R¹⁶)₂,—R¹⁷—O—R¹⁸—C(O)N(R¹⁶)₂, —R¹⁷—O—R¹⁸—N(R¹⁶)₂, and —R¹⁷—S(O)_(t)N(R¹⁶)₂(where t is 1 or 2), where each R¹⁶ is independently hydrogen, alkyl,haloalkyl, cycloalkyl, cycloalkylalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl or optionally substituted heteroarylalkyl, each R¹⁷ isindependently a direct bond or a straight or branched alkylene oralkenylene chain, and R¹⁸ is a straight or branched alkylene oralkenylene chain; R⁶, R⁷ and R⁸ are each independently alkyl, haloalkyl,or —R¹³—OR¹⁵; R¹⁶ is alkyl, halo or haloalkyl; R¹³ is selected from thegroup consisting of a direct bond or an optionally substituted straightor branched alkylene chain; R¹⁴ is an optionally substituted straight orbranched alkylene chain; and R¹⁵ is selected from the group consistingof hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl, and optionally substituted heteroarylalkyl.
 4. The compoundof claim 3 wherein: n is 0; m is 0 to 1; R¹, R², R⁴ and R⁵ are eachindependently hydrogen, alkyl, cycloalkylalkyl, or —R¹⁴—OR¹⁵; R^(3a),R^(3b), R^(3c), R^(3d) and R^(3e) are each independently selected fromthe group consisting of hydrogen, alkyl, halo, haloalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted heteroaryl, or optionally substitutedheteroarylalkyl; R⁶, R⁷ and R⁸ are each independently alkyl, haloalkyl,or —R¹³—OR¹⁵; R¹⁰ is alkyl, halo or haloalkyl; R¹³ is selected from thegroup consisting of a direct bond or an optionally substituted straightor branched alkylene chain; R¹⁴ is an optionally substituted straight orbranched alkylene chain; and R¹⁵ is selected from the group consistingof hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl, and optionally substituted heteroarylalkyl.
 5. The compoundof claim 4 wherein: n is 0; m is 0 to 1; R¹, R², R⁴ and R⁵ are eachindependently hydrogen, alkyl, cycloalkylalkyl, or —R¹⁴—OR¹⁵; R^(3d),R^(3b), and R^(3d) are each hydrogen; R^(3c) and R^(3d) are eachindependently selected from the group consisting of hydrogen, alkyl,halo, haloalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl, oroptionally substituted heteroarylalkyl; R⁶, R⁷ and R⁸ are eachindependently alkyl, haloalkyl, or —R¹³—OR¹⁵; R¹⁰ is alkyl, halo orhaloalkyl; R¹³ is selected from the group consisting of a direct bond oran optionally substituted straight or branched alkylene chain; R¹⁴ is anoptionally substituted straight or branched alkylene chain; and R¹⁵ isselected from the group consisting of hydrogen, alkyl, haloalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl, and optionallysubstituted heteroarylalkyl.
 6. The compound of claim 5 which is(1S,2S,3R,5S)-2-(5-chloro-2-(4-morpholinophenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide.7. The compound of claim 3 wherein: n is 0; m is 0 to 1; R¹, R², R⁴ andR⁵ are each independently hydrogen, alkyl, cycloalkylalkyl, or—R¹⁴—OR¹⁵; R³⁸, R^(3b), R^(3c), R^(3d) and R^(3e) are each independentlyselected from the group consisting of hydrogen, alkyl, halo, haloalkyl,—R¹⁷—OR¹⁶, —R¹⁷—N(R¹⁶)₂, —R¹⁷—C(O)R¹⁶, —R¹⁷—C(O)OR¹⁶, —R¹⁷—C(O)N(R¹⁶)₂,—R¹⁷—O—R¹⁸—C(O)N(R¹⁶)₂, —R¹⁷—O—R¹⁸—N(R¹⁶)₂, and —R¹⁷—S(O)_(t)N(R¹⁶)₂(where t is 1 or 2), where each R¹⁶ is independently hydrogen, alkyl,haloalkyl, cycloalkyl, cycloalkylalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl or optionally substituted heteroarylalkyl, each R¹⁷ isindependently a direct bond or a straight or branched alkylene oralkenylene chain, and R¹⁸ is a straight or branched alkylene oralkenylene chain; R⁶, R⁷ and R⁸ are each independently alkyl, haloalkyl,or —R¹³—OR¹⁵; R¹⁰ is alkyl, halo or haloalkyl; R¹³ is selected from thegroup consisting of a direct bond or an optionally substituted straightor branched alkylene chain; R¹⁴ is an optionally substituted straight orbranched alkylene chain; and R¹⁵ is selected from the group consistingof hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl, and optionally substituted heteroarylalkyl.
 8. The compoundof claim 7 wherein: n is 0; m is 0 to 1; R¹, R², R⁴ and R⁵ are eachindependently hydrogen, alkyl, cycloalkylalkyl, or —R¹⁴—OR¹⁵; R^(3a),R^(3b) and R^(3e) are each hydrogen; R^(3c) and R^(3d) are eachindependently selected from the group consisting of hydrogen, alkyl,halo, haloalkyl, —R¹⁷—OR¹⁶, —R¹⁷—N(R¹⁶)₂, —R¹⁷—C(O)R¹⁶, —R¹⁷—C(O)OR¹⁶,—R¹⁷—C(O)N(R¹⁶)₂, —R¹⁷—O—R¹⁸—C(O)N(R¹⁶)₂, —R¹⁷—O—R¹⁸—N(R¹⁶)₂, and—R¹⁷—S(O)_(t)N(R¹⁶)₂ (where t is 1 or 2), where each R¹⁶ isindependently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted heteroaryl or optionally substitutedheteroarylalkyl, each R¹⁷ is independently a direct bond or a straightor branched alkylene or alkenylene chain, and R¹⁸ is a straight orbranched alkylene or alkenylene chain; R⁶, R⁷ and R⁸ are eachindependently alkyl, haloalkyl, or —R¹³—OR¹⁵; R¹⁰ is alkyl, halo orhaloalkyl; R¹³ is selected from the group consisting of a direct bond oran optionally substituted straight or branched alkylene chain; R¹⁴ is anoptionally substituted straight or branched alkylene chain; and R¹⁵ isselected from the group consisting of hydrogen, alkyl, haloalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl, and optionallysubstituted heteroarylalkyl.
 9. The compound of claim 8 selected fromthe group consisting of:2S,3R,5S)-2-(5-chloro-2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide;and2S,3R,5S)-2-(5-chloro-2-(3-fluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)pyrimidin-4-ylamino)-N,2,6,6-tetramethylbicyclo[3.1.1]heptane-3-carboxamide.10. A pharmaceutical composition comprising a pharmaceuticallyacceptable excipient and a therapeutically effective amount of acompound of formula (Ib):

wherein: n is 0 to 7; m is 0 to 2; R¹, R², R⁴ and R⁵ are eachindependently hydrogen, alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, —R¹⁴—OR¹⁵, —C(O)R¹⁵ or —C(O)N(R¹¹)R¹²; or R⁴ and R⁵,together with the nitrogen to which they are attached, form anoptionally substituted N-heteroaryl or an optionally substitutedN-heterocyclyl; R^(3a), R^(3b), R^(3c), R^(3d) and R^(3e) are eachindependently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, cyano,nitro, optionally substituted aryl, optionally substituted aralkyl,optionally substituted aralkenyl, optionally substituted aralkynyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionallysubstituted cycloalkylalkynyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheterocyclylalkenyl, optionally substituted heterocyclylalkynyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heteroarylalkenyl, optionallysubstituted heteroarylalkynyl, —R¹⁷—OR¹⁶, —R¹⁷—OC(O)—R¹⁶, —R¹⁷—N(R¹⁶)₂,—R¹⁷—C(O)R¹⁶, —R¹⁷—C(O)OR¹⁶, —R¹⁷—C(O)N(R¹⁶)₂, —R¹⁷—O—R¹⁸—C(O)N(R¹⁶)₂,—R¹⁷—O—R¹⁸—N(R¹⁶)₂, —R¹⁷—N(R¹⁶)C(O)OR¹⁶, —R¹⁷—N(R¹⁶)C(O)R¹⁶,—R¹⁷—N(R¹⁶)S(O)_(t)R¹⁶ (where t is 1 or 2), —R¹⁷—S(O)_(t)OR¹⁶ (where tis 1 or 2), —R¹⁷—S(O)_(p)R¹⁶ (where p is 0, 1 or 2), and—R¹⁷—S(O)_(t)N(R¹⁶)₂ (where t is 1 or 2), where each R¹⁶ isindependently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted heteroaryl or optionally substitutedheteroarylalkyl, each R¹⁷ is independently a direct bond or a straightor branched alkylene or alkenylene chain, and R¹⁸ is a straight orbranched alkylene or alkenylene chain; R⁶, R⁷ and R⁸ are eachindependently alkyl, haloalkyl, or —R¹³—OR¹⁵; each R⁹ and R¹⁰ isindependently alkyl, halo, haloalkyl, aryl or aralkyl; R¹¹ and R¹² areeach independently selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl,hydroxyalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionallysubstituted cycloalkylalkynyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheterocyclylalkenyl, optionally substituted heterocyclylalkynyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heteroarylalkenyl, optionallysubstituted heteroarylalkynyl, —R¹⁴— OR¹⁵, —R¹⁴—CN, —R¹⁴—NO₂,—R¹⁴—N(R¹⁵)₂, —R¹⁴—C(O)OR¹⁵ and —R¹⁴—C(O)N(R¹⁵)₂; optionally, R¹¹ andR¹², together with the nitrogen to which they are attached, form anoptionally substituted N-heteroaryl or an optionally substitutedN-heterocyclyl; R¹³ is independently selected from the group consistingof a direct bond, an optionally substituted straight or branchedalkylene chain, an optionally substituted straight or branchedalkenylene chain and an optionally substituted straight or branchedalkynylene chain; each R¹⁴ is independently selected from the groupconsisting of an optionally substituted straight or branched alkylenechain, an optionally substituted straight or branched alkenylene chainand an optionally substituted straight or branched alkynylene chain; andeach R¹⁵ is independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted aralkenyl, optionally substituted aralkynyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted cycloalkylalkenyl, optionally substitutedcycloalkylalkynyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substitutedheterocyclylalkenyl, optionally substituted heterocyclylalkynyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heteroarylalkenyl, andoptionally substituted heteroarylalkynyl; as an isolated stereoisomer ormixture thereof, or a pharmaceutically acceptable salt thereof.
 11. Amethod of treating a disease or condition associated with Axl catalyticactivity in a mammal, wherein the method comprises administering to themammal a therapeutically effective amount of a compound of formula (Ib):

wherein: n is 0 to 7; m is 0 to 2; R¹, R², R⁴ and R⁵ are eachindependently hydrogen, alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, —R¹⁴—OR¹⁵, —C(O)R¹⁵ or —C(O)N(R¹¹)R¹²; or R⁴ and R⁵,together with the nitrogen to which they are attached, form anoptionally substituted N-heteroaryl or an optionally substitutedN-heterocyclyl; R^(3a), R^(3b), R^(3c), R^(3d) and R^(3e) are eachindependently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, cyano,nitro, optionally substituted aryl, optionally substituted aralkyl,optionally substituted aralkenyl, optionally substituted aralkynyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionallysubstituted cycloalkylalkynyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheterocyclylalkenyl, optionally substituted heterocyclylalkynyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heteroarylalkenyl, optionallysubstituted heteroarylalkynyl, —R¹⁷—OR¹⁶, —R¹⁷—OC(O)—R¹⁶, —R¹⁷—N(R¹⁶)₂,—R¹⁷—C(O)R¹⁶, —R¹⁷—C(O)OR¹⁶, —R¹⁷—C(O)N(R¹⁶)₂, —R¹⁷—O—R¹⁵—C(O)N(R¹⁶)₂,—R¹⁷—O—R¹⁵—N(R¹⁶)₂, —R¹⁷—N(R¹⁶)C(O)OR¹⁶, —R¹⁷—N(R¹⁶)C(O)R¹⁶,—R¹⁷—N(R¹⁶)S(O)_(t)R¹⁶ (where t is 1 or 2), —R¹⁷—S(O)_(t)OR¹⁶ (where tis 1 or 2), —R¹⁷—S(O)_(p)R¹⁶ (where p is 0, 1 or 2), and—R¹⁷—S(O)_(t)N(R¹⁶)₂ (where t is 1 or 2), where each R¹⁶ isindependently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted heteroaryl or optionally substitutedheteroarylalkyl, each R¹⁷ is independently a direct bond or a straightor branched alkylene or alkenylene chain, and R¹⁸ is a straight orbranched alkylene or alkenylene chain; R⁶, R⁷ and R⁸ are eachindependently alkyl, haloalkyl, or —R¹³—OR¹⁵; each R⁹ and R¹⁰ isindependently alkyl, halo, haloalkyl, aryl or aralkyl; R¹¹ and R¹² areeach independently selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl,hydroxyalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionallysubstituted cycloalkylalkynyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheterocyclylalkenyl, optionally substituted heterocyclylalkynyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heteroarylalkenyl, optionallysubstituted heteroarylalkynyl, —R¹⁴—OR¹⁵, —R¹⁴—CN, —R¹⁴—NO₂,—R¹⁴—N(R¹⁵)₂, —R¹⁴—C(O)OR¹⁵ and —R¹⁴—C(O)N(R¹⁵)₂; optionally, R¹¹ andR¹², together with the nitrogen to which they are attached, form anoptionally substituted N-heteroaryl or an optionally substitutedN-heterocyclyl; R¹³ is independently selected from the group consistingof a direct bond, an optionally substituted straight or branchedalkylene chain, an optionally substituted straight or branchedalkenylene chain and an optionally substituted straight or branchedalkynylene chain; each R¹⁴ is independently selected from the groupconsisting of an optionally substituted straight or branched alkylenechain, an optionally substituted straight or branched alkenylene chainand an optionally substituted straight or branched alkynylene chain; andeach R¹⁵ is independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted aralkenyl, optionally substituted aralkynyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted cycloalkylalkenyl, optionally substitutedcycloalkylalkynyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substitutedheterocyclylalkenyl, optionally substituted heterocyclylalkynyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heteroarylalkenyl; andoptionally substituted heteroarylalkynyl; as an isolated stereoisomer ormixture thereof, or a pharmaceutically acceptable salt thereof.
 12. Themethod of claim 11 wherein the disease or condition is alleviated by themodulation of Axl activity.
 13. The method of claim 11 wherein thedisease of condition is alleviated by a increase in Axl activity. 14.The method of claim 11 wherein the disease of condition is alleviated bya decrease in Axl activity.
 15. The method of claim 14 wherein thedisease or condition is selected from the group consisting of rheumatoidarthritis, vascular disease, vascular injury, psoriasis, visualimpairment due to macular degeneration, diabetic retinopathy,retinopathy of prematurity, kidney disease, osteoporosis, osteoarthritisand cataracts.
 16. The method of claim 14, wherein a manifestation ofthe disease or condition is solid tumor formation in said mammal. 17.The method of claim 16, wherein the disease or condition is selectedfrom the group consisting of breast carcinoma, renal carcinoma,endometrial carcinoma, ovarian carcinoma, thyroid carcinoma, non-smallcell lung carcinoma, melanoma, prostate carcinoma, sarcoma, gastriccancer and uveal melanoma.
 18. The method of claim 14, wherein amanifestation of the disease or condition is liquid tumor formation insaid mammal.
 19. The method of claim 18, wherein the disease orcondition is myeloid leukemia or lymphoma.
 20. The method of claim 14wherein the disease or condition is endometriosis.